Personalized cosmetic system

ABSTRACT

Systems and methods disclosed for recommending beauty products for a subject by using a DNA sequencer to generate genetic information; aggregating genetic information, beauty trend data, and cosmetic product response from a patient population; deep learning with a computer to generate at least one computer implemented classifier that predicts matching beauty products based on the genetic information, beauty trend data, and cosmetic product response from a patient population; and recommending one or more beauty products for the subject.

BACKGROUND

The present invention relates to the field of genetic basedbeauty/healthcare product selection.

Existing beauty products are not optimized for each person. For example,in improving beauty, proper skin tone determination is key. The skin'sundertone is the warm, cool, or neutral hue that shows through thesurface color of skin. Although the surface color of skin changesdepending on sun exposure and other skin conditions like rosacea andacne, the skin's undertone remains consistent. The undertone is warm,cool or neutral is the key to ensuring that your foundation matches skinand that other makeup products apply to look natural. When foundationdoesn't properly match skin's undertone, the color stands out as orangeto copper, pink to rose, or ashen. In addition to beauty applications,the skin color is also needed in protecting against skin cancer.

SUMMARY

In one aspect, systems methods disclosed for recommending health/beautyproducts for a subject by using a genetic machine such asspectrophotometer or a DNA sequencer to generate genetic information;aggregating genetic information, and cosmetic product response from apatient population; deep learning with a computer to generate at leastone computer implemented classifier that predicts matching beautyproducts based on the genetic information, beauty trend data, andcosmetic product response from a patient population; and recommendingone or more beauty products for the subject.

In another aspect, a system includes a cosmetic or health additivesubstance to be consumed by a subject and one or more indicia labelingthe substance with: genomic biomarkers; material exposure and clinicalresponse variability; risk for adverse events; genotype-specific dosing;polymorphic cosmetic material target and disposition genes; andtreatment based on the biomarker.

Advantages of the system may include one or more of the following. Thesystems and methods use DNA markers together with proprietary DNADatabase and algorithm for personalized cosmetic matching by defining aperson's skin traits. The systems-based approach combines theinteraction of markers in specific genes directly affecting skinpigmentation together with global population markers and accounts forepistatic gene-gene as well as gene-by-environment interactions. Thesystem provides a comprehensive spectrum of variation in skin colorgenetic markers and corresponding highly specific skin color shades toenhance beauty for women. Additionally, the system can avoid allergicreactions. It can also recommend perfumes based on DNA. This will lowerthe costs that come about due to adverse cosmetic material side effectsand prescription of cosmetic materials that have been proven ineffectivein certain genotypes. Cosmetic material companies can develop andlicense a cosmetic material specifically intended for those who are thesmall population genetically at risk for adverse side effects.

Additional aspects of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. The aspectsof the invention will be realized and attained by means of the elementsand combinations particularly pointed out in the appended claims. It isto be understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute partof this specification, illustrate embodiments of the invention andtogether with the description, serve to explain the principles of theinvention. The embodiments illustrated herein are presently preferred,it being understood, however, that the invention is not limited to theprecise arrangements and instrumentalities shown, wherein:

FIG. 1A shows exemplary DNA and skin tone illustrations;

FIG. 1B show exemplary cosmetic DNA mapping and cosmetic recommendationprocess;

FIG. 1C shows an exemplary system to collect lifestyle and genetic datafrom various populations for subsequent cosmetic prediction andrecommendation to similarly situated users.

FIG. 2 is a schematic illustration of a data processing systemconfigured for computer management genetic information, precisionmedication and cosmetic material interaction information retrieval;

FIG. 3 is a flow chart illustrating a process for pharmacogeneticscosmetic material interaction information retrieval;

FIG. 4 shows a big data learning machine to process genetic data anddetermine pharmacogenetics relationship among genes and cosmeticmaterials for cosmetic material interaction purposes;

FIG. 5A shows various common aberrations in cancer genomes;

FIG. 5B shows an exemplary system to detect the evolutionary paths ofescape;

FIG. 5C shows an exemplary model generated by the system of FIG. 5B;

FIG. 5D shows an exemplary a heterogeneous collection of normal cellsand skin cancer subclones developed during an evolutionary history of atumor.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise noted, technical terms are used according toconventional usage. Definitions of common terms in molecular biology maybe found in Benjamin Lewin, Genes V, published by Oxford UniversityPress, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), TheEncyclopedia of Molecular Biology, published by Blackwell Science Ltd.,1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biologyand Biotechnology: a Comprehensive Desk Reference, published by VCHPublishers, Inc., 1995 (ISBN 1-56081-569-8). As used herein and in theappended claims, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood to one of ordinary skill in the art towhich this disclosure belongs. “Comprising” means “including.” Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety.

Embodiments of the present invention provide a method, system andcomputer program product for computer identification (scanning orimaging of cosmetic materials) for cosmetic material interactioninformation retrieval. In accordance with an embodiment of the presentinvention, multiple different cosmetic materials can be scanned orimaged to detect identifiable content disposed on the different cosmeticmaterials. Each cosmetic material can be compared to a data store ofcosmetic material information to identify each cosmetic material.Thereafter, pharmacogenetics data and cosmetic material interaction datacan be retrieved for each identified cosmetic material. Further, knowncosmetic material-cosmetic material interactions and genetic impacts forthe identified cosmetic materials can be determined and a report can beprovided to include the known cosmetic material-cosmetic materialinteractions. In this way, precision medicine and cosmeticmaterial-cosmetic material interactions resulting from the use of themultiple different cosmetic materials can be determined without recourseto a voluminous text of cosmetic material interactions.

FIG. 1B show an exemplary process for computer detection of substancesor cosmetic materials for cosmetic material interaction informationretrieval. Turning now to FIG. 1B, 110 operation includes capture facialimage or video. 120 operation is used to identify visual skin tone fromthe image. In 130 a swipe of patient DNA is captured. In 140 the DNA isprocessed for user markers of interest relating to skin, for example. In150 the process retrieves cosmetic material data and cosmetic materialinteraction data for each of the imaged substances and determinesrelative interactions between substances. In 160 the process measuresattributes of the cosmetic products and store in database. In 170, theprocess applies pharmacogenomic information to the cosmeticmaterial-cosmetic material interaction data. In 180 the processidentifies beauty products and makes recommendations based on attributesof the cosmetic products and selects the best matching cosmetic productor health product. In 190, the process renders DNA based beauty productrecommendation and/or health recommendation (such as cancer risk) in areport such as a paper report or a graphical user interface display.

While FIG. 1B discusses capturing cosmetic material interaction, theprocess can be used to capture environmental factors of FIG. 1A. In yetother embodiments, the process cryptographically reads substance contentfrom RF tag or barcode on a secure cosmetic container bottle andidentifies content for the cosmetic substance. Identified substances areadded to an interaction list and the process determines if additionalsubstances remain to be scanned (RF/Bar Code) and continues processing.The interaction list now populated by a list of scanned substances isprocessed. Next, the process retrieves cosmetic material data andcosmetic material interaction data for each of the scanned substancesand determines relative interactions between substances. The processreceives genetic scans for subjects. The process applies pharmacogenomicinformation to the cosmetic material-gene interaction data and selectsthe best medication and identify people who need an unusually high orlow dose. Relative interactions can be rendered within a report such asa paper report or a graphical user interface display.

In some examples, one or more pages describing the recommendedpersonalized treatment serums and supplements based on the individualshigh and medium risk category results are listed. For example, followingrecommendations for non-customized products, one or more custom-designedproducts may be recommended based on the DNA report. Theserecommendations may include a combination of treatmentserums/nutritional products that address the individual strengths andweaknesses of the individuals skin as determined by their DNA report.These customized recommendations many include products such as:

a. Serums:

1. Vitamin C Treatment Serum

2. Hyaluronic Moisture Treatment Serum

3. Wrinkle Treatment Serum

4. Calming Treatment Serum

b. Supplements:

1. Antioxidant Defense

2. Glycation Defense

3. Sun Defense

4. Collagen Defense

5. Inflammation Defense

The determination as to which products will be custom recommended may bebased on an algorithmic protocol that matches the ingredients in theproducts to the weakness that the person's DNA analysis reveals asidentified in their medium or high risk categories. This may beprogrammed based on an algorithm into the computer system that generatesthe DNA report. High risk categories are an influencing category asrecommendations to follow as they provide the individual the greatestopportunity to improve the health and appearance of their skin followedby the medium risk category recommendations. For instance, if a personis determined to be medium or high risk for collagen, products will berecommended that support healthy collagen production and maintenance inthe skin. The ingredients in the products that support healthy collagenproduction and maintenance will be selected and put into the skin careproducts and nutritional supplements based on clinical research thatsupports the clinical effectiveness of the ingredients included in theproduct on the category to which it applies. Raw ingredient selectionmay be supported by clinical research regarding the effectiveness of theingredient as identified in both peer-reviewed literature as well asclinical studies. These human clinical studies may be performed by a rawingredient manufacturer to validate and support the effectiveness of theingredient in well-controlled human trials. In some examples, productrecommendations will be organized into high risk and medium riskcategories on the report for ease of understanding and product selectionby the individual. In some examples, if a product is already listedunder a high-risk category, it will not be relisted under a medium riskcategory as it is already selected by the algorithm and recommended. Insome examples, ingredients will be upgraded and changed on a regularbasis based on the current science and literature as new ingredientswith better product effectiveness become available in the raw ingredientmarketplace.

In some examples, following the formulation process and algorithmicrecommendations above, products may be clinically used and evaluated ina clinical practice to ensure that the effectiveness, aesthetic appealand client satisfaction are of the highest standards possible.

It is contemplated that disclosed products may be distributed into themarketplace through various distribution models which may include directto consumer, business to business, direct sales through a Multilevelmarketing program, television/infomercial. In some examples, afterreviewing the report, the report may be provided to the subject, eitherdirectly or indirectly (e.g., electronically or standard mail) and anoptional customer service meeting/call is set up for those who desire togo over the results and product recommendations, and/or have questionsregarding their report

In some embodiments, a method of characterizing a subject's skin isprovided which includes generating a personalized skin profile. In someexamples, generating a personalized skin profile includes determining asubject's genetic potential in at least one area of skin health orappearance by analyzing one or more skin health-associated singlenucleotide polymorphisms (SNPs) or other genetic marker associated withthe particular area of skin health or appearance being assessed in abiological sample obtained from the subject. In some examples, asubject's genetic potential is determined in one to five or more areasof skin health by analyzing one or more skin health-associated SNPs orother genetic markers associated with the one to five or more areas ofskin health in a sample obtained from the subject. The one or more areasof skin health can include assessing the following or more factors:collagen formation, sun protection, antioxidant protection, glycationprotection and inflammation control. The generated skin profile revealsthe subject's genetic strengths, weaknesses and/or risks related to theone or more areas of skin health thereby allowing a personalizedskincare and/or nutritional regimen to be developed and implemented. Insome examples, a disclosed method of characterizing a subject's skinfurther includes identifying SNPs or other genetic markers associatedwith a particular area of skin health. For example, SNPs associated witha particular area of skin health can be identified by searching thepublicly available SNP on the Worldwide Web (see for example, domainname ncbi.nlm.nih.gov/snp; domain name ncbi.nlm.nih.gov/projects/SNP/;or domain name snp.cshl.org/) and determining SNPs associated withparticular skin conditions. In some examples, a disclosed method ofcharacterizing a subject's skin further includes providing the resultsof the characterization study to the subject. In some examples adisclosed method of characterizing a subject's skin further includesrecommending and/or providing one or more skincare treatments to thesubject based upon the skin profile generated by the characterizationanalysis. In some examples, the disclosed method of characterizing asubject's skin is performed at home. For example, a subject utilizes akit designed to allow a subject to generate a skin profile by obtaininga DNA sample at home with the kit which includes an instruction booklet,a questionnaire, a DNA swab, a collection envelope with dessicant toplace the specimen in after collection. This sample is then sent foranalysis and evaluation and a report is generated for the individual.

In some examples, the kit includes a means for obtaining a biologicalsample, such a buccal swab and a collection vial which allows the sampleto be stored during shipment to the analysis laboratory. Theinstructions for use can in any form, such as in a pamphlet or providedvia electronic means, such as a website on the Worldwide Web.

In some examples, the disclosed method includes identifying one or more,such as one, two, three, four, five or more, categories of skin healthand clinical studies to prove these categories have an impact on theskin (glycation causes aging, etc). For example, one or more SNPs isidentified by identifying an SNP with an RS number that affects theenzyme or function in each category. Studies, such as clinical studies,are performed to identify the variations of the base at this location tovalidate that it is an SNP versus an infrequent variant and the clinicalsignificance of this (it affects collagenase, etc.) Tests are thenperformed to identify which base patterns are protective versus riskpromoting. The impact of the one or more SNPs identified on eachskincare category is determined, such as by use of an algorithm.Additional studies are then performed to show that the disclosedtreatments/protocols impact that area of skin health.

FIG. 1C shows an exemplary system to collect skin color, lifestyle andgenetic data from various populations for subsequent prediction andrecommendation to similarly situated users. The system collectsattributes associated with individuals that co-occur (i.e.,co-associate, co-aggregate) with attributes of interest, such asspecific disorders, behaviors and traits. The system can identifycombinations of attributes that predispose individuals toward having ordeveloping specific disorders, behaviors and traits of interest,determining the level of predisposition of an individual towards suchattributes, and revealing which attribute associations can be added oreliminated to effectively modify his or her lifestyle to avoid medicalcomplications. Details captured can be used for improving individualizeddiagnoses, choosing the most effective therapeutic regimens, makingbeneficial lifestyle changes that prevent disease and promote health,and reducing associated health care expenditures. It is also desirableto determine those combinations of attributes that promote certainbehaviors and traits such as success in sports, music, school,leadership, career and relationships. For example, the system capturesinformation on epigenetic modifications that may be altered due toenvironmental conditions, life experiences and aging. Along with acollection of diverse nongenetic attributes including physical,behavioral, situational and historical attributes, the system canpredict a predisposition of a user toward developing a specificattribute of interest. In addition to genetic and epigenetic attributes,which can be referred to collectively as pangenetic attributes, numerousother attributes likely influence the development of traits anddisorders. These other attributes, which can be referred to collectivelyas non-pangenetic attributes, can be categorized individually asphysical, behavioral, or situational attributes.

FIG. 1C displays one embodiment of the attribute categories and theirinterrelationships according to the present invention and illustratesthat physical and behavioral attributes can be collectively equivalentto the broadest classical definition of phenotype, while situationalattributes can be equivalent to those typically classified asenvironmental. In one embodiment, historical attributes can be viewed asa separate category containing a mixture of genetic, epigenetic,physical, behavioral and situational attributes that occurred in thepast. Alternatively, historical attributes can be integrated within thegenetic, epigenetic, physical, behavioral and situational categoriesprovided they are made readily distinguishable from those attributesthat describe the individual's current state. In one embodiment, thehistorical nature of an attribute is accounted for via a time stamp orother time based marker associated with the attribute. As such, thereare no explicit historical attributes, but through use of time stamping,the time associated with the attribute can be used to make adetermination as to whether the attribute is occurring in what would beconsidered the present, or if it has occurred in the past. Traditionaldemographic factors are typically a small subset of attributes derivedfrom the phenotype and environmental categories and can be thereforerepresented within the physical, behavioral and situational categories.

An individual possesses many associated attributes which may becollectively referred to as an ‘attribute profile’ associated with thatindividual. In one embodiment, an attribute profile can be considered asattributes that are present (i.e., occur) in that profile, as well asbeing comprised of the various combinations (i.e., combinations andsubcombinations) of those attributes. The attribute profile of anindividual is preferably provided to embodiments of the presentinvention as a dataset record whose association with the individual canbe indicated by a unique identifier contained in the dataset record. Anactual attribute of an individual can be represented by an attributedescriptor in attribute profiles, records, datasets, and databases.Herein, both actual attributes and attribute descriptors may be referredto simply as attributes. In one embodiment, statistical relationshipsand associations between attribute descriptors are a direct result ofrelationships and associations between actual attributes of anindividual. In the present disclosure, the term ‘individual’ can referto a singular group, person, organism, organ, tissue, cell, virus,molecule, thing, entity or state, wherein a state includes but is notlimited to a state-of-being, an operational state or a status.Individuals, attribute profiles and attributes can be real and/ormeasurable, or they may be hypothetical and/or not directly observable.

Since the system captures information from various diverse populations,the data can be mined to discover combinations of attributes regardlessof number or type, in a population of any size, that causepredisposition to an attribute of interest. The ability to accuratelydetect predisposing attribute combinations naturally benefits from beingsupplied with datasets representing large numbers of individuals andhaving a large number and variety of attributes for each. Nevertheless,the present invention will function properly with a minimal number ofindividuals and attributes. One embodiment of the present invention canbe used to detect not only attributes that have a direct (causal) effecton an attribute of interest, but also those attributes that do not havea direct effect such as instrumental variables (i.e., correlativeattributes), which are attributes that correlate with and can be used topredict predisposition for the attribute of interest but are not causal.For simplicity of terminology, both types of attributes are referred toherein as predisposing attributes, or simply attributes, that contributetoward predisposition toward the attribute of interest, regardless ofwhether the contribution or correlation is direct or indirect.

The multiplex-SNP-assay consists of a multiplex-PCR that amplifies eightregions. The amplification is checked on the Agilent Bioanalyzer. ThePCR products are purified by using the ExoSAP-IT kit to preventremaining primers or dNTPs from interfering with the following step. TheSBPE reaction is performed by using the SNaPshot Multiplex kit. The SBPEproduct is treated with Shrimp Alkaline Phosphatase to dephosphorylatethe fluorescently labeled dNTPs. This prevents further reactions of thedNTPs that could lead to extra-peaks in the electropherogram of themulticolor capillary electrophoresis. The products of themultiplex-SNP-assay are separated by color and size and detected usingthe 3130x1 multicolor capillary electrophoresis. Data analysis isperformed with GeneMapper.

The process shown in FIG. 1B can be implemented within a data processingsystem. In further illustration, FIG. 2 schematically depicts a dataprocessing system configured for computer visualization of cosmeticmaterials for cosmetic material interaction information retrieval. Thesystem can include a host computing platform 202 coupled to a camera 220such as a digital still camera or digital video camera. The camera 220can be focused on a marshalling point 240 provided by a marshallingapparatus 230, for example gravity feed or isolation chamber orminiature conveyor belt. The host computing platform 202 also can becommunicatively coupled a cosmetic material image data store 250 ofknown substances and corresponding known identifying content visuallydisposed on the known substances. The host computing platform 202additionally can be communicatively coupled to a cosmetic materialinteraction data store 260 providing cosmetic material interaction datafor different substances relative to other substances includingprescription and over-the-counter cosmetic materials, vitamins andherbal remedies, and food products.

In one embodiment of FIG. 2 , multiple different substances such ascosmetic materials, over-the-counter health materials or even vitaminsand herbal remedies can be provided to a marshalling apparatus such as agravity feed or miniature conveyor belt or even a chamber. Themarshalling apparatus can isolate an individual one of the differentsubstances for imaging by camera 220, for example a charge coupleddevice (CCD) driven digital camera or video recorder. The camera 220 cancapture an image of each individual one of the different substances110A, 110B, 110N and computer visualization for cosmetic materialinteraction information retrieval logic 300 can process each capturedimage to detect identifying content disposed on each of the differentsubstances such as a pill marking or code. The computer visualizationfor cosmetic material interaction information retrieval logic 300 inturn can compare the identified content to a data store of knownsubstances 140 to identify each of the different substances. Thecomputer can lookup not only known cosmetic material interactions foreach of the different substances, but also known cosmetic materialinteractions between the identified ones of the substances andpharmacogenetics impact on the individual patient. Thereafter, acosmetic material interaction report can be produced indicating theknown cosmetic material interactions between the identified ones of thesubstances.

The host computing platform 202 can support the execution of computerscanning or visualization for cosmetic material interaction informationretrieval logic 270. The logic can include program code enabled toacquire imagery of different substances in the marshalling point 240.The program code further can be enabled to locate and retrieveidentifying content disposed on the different substances and to look upthe identifying content in the cosmetic material image data store 250 inorder to identify each of the substances. The program code yet furthercan be enabled to retrieve from cosmetic material interaction data store260 cosmetic material interactions for each of the identified substancesand to particularly correlate the retrieved cosmetic materialinteractions to different ones of the substances so that relativecosmetic material interactions can be determined for the substances.Finally, the program code can be enabled to render a report of cosmeticmaterial interaction data in a graphical user interface display 280 ofcosmetic material interaction data.

The computing platform 202 also receives pharmacogenetics interaction282. Notably, the host computing platform 202 can support the executionof computer visualization for pharmacogenetics interaction informationretrieval logic 272. Genetic information is captured by high speed genesequencing machine 210 that uploads gene data to a cloud computingnetwork 212. The doctors, pharmacists, or consumers can access DNAinformation using mobile computers such as smart phone 214, for example.

The system can have wireless communication 292 with the medication'slabels. For example, the labels can have RF tags or NFC tags thatprovide upon inquiry FDA required labeling contents. In one embodiment,the content can be genomic biomarkers; cosmetic material exposure andclinical response variability; risk for adverse events;genotype-specific dosing; polymorphic cosmetic material target anddisposition genes; and treatment based on the biomarker. NFC tags arepassive devices and operate without a power supply of their own and arereliant on an active device to come into range before they areactivated. To power these NFC tags, electromagnetic induction is used tocreate a current in the passive device. Active devices, such as a readeror a smartphone, are responsible for generating the magnetic field witha simple coil of wire, which produces magnetic fields perpendicular tothe flow of the alternating current in the wire. To reduce power, NFCoperates over just a few inches, rather than the meters in other typesof wireless communication.

The system can be used to provide personalized medicine through customchemical compounding 294 or custom production of a cosmetic materialwhose various properties (e.g. dose level, ingredient selection, routeof administration, etc.) are selected and crafted for an individualpatient (in contrast to mass-produced unit doses or fixed-dosecombinations).

The genetic scan in 70 can be generated by gene sequencing machines. DNAsequencing is the process of determining the precise order ofnucleotides within a DNA molecule. It includes any method or technologythat is used to determine the order of the four bases—adenine, guanine,cytosine, and thymine—in a strand of DNA. Various high speed sequencerscan be used. For example, Nanopore DNA sequencing is based on thereadout of electrical signals occurring at nucleotides passing byalpha-hemolysin pores covalently bound with cyclodextrin. The DNApassing through the nanopore changes its ion current. Oxford NanoporeTechnologies offers a handheld sequencer capable of generating more than150 megabases of sequencing data in one run. More information isdisclosed in U.S. Pat. No. 9,127,313, the content of which isincorporated by reference.

Another approach uses measurements of the electrical tunneling currentsacross single-strand DNA as it moves through a channel Depending on itselectronic structure, each base affects the tunneling currentdifferently, allowing differentiation between different bases. The useof tunneling currents has the potential to sequence orders of magnitudefaster than ionic current methods and the sequencing of several DNAoligomers and micro-RNA has already been achieved. Sequencing byhybridization is a non-enzymatic method that uses a DNA microarray. Asingle pool of DNA whose sequence is to be determined is fluorescentlylabeled and hybridized to an array containing known sequences. Stronghybridization signals from a given spot on the array identify itssequence in the DNA being sequenced. Mass spectrometry may be used todetermine DNA sequences. Matrix-assisted laser desorption ionizationtime-of-flight mass spectrometry, or MALDI-TOF MS, has specifically beeninvestigated as an alternative method to gel electrophoresis forvisualizing DNA fragments. With this method, DNA fragments generated bychain-termination sequencing reactions are compared by mass rather thanby size. The mass of each nucleotide is different from the others andthis difference is detectable by mass spectrometry. Single-nucleotidemutations in a fragment can be more easily detected with MS than by gelelectrophoresis alone. MALDI-TOF MS can more easily detect differencesbetween RNA fragments, so researchers may indirectly sequence DNA withMS-based methods by converting it to RNA first. In microfluidic Sangersequencing the entire thermocycling amplification of DNA fragments aswell as their separation by electrophoresis is done on a single glasswafer (approximately 10 cm in diameter) thus reducing the reagent usageas well as cost. Microscopy-based technique directly visualizes thesequence of DNA molecules using electron microscopy. RNAP sequencing isbased on use of RNA polymerase (RNAP), which is attached to apolystyrene bead. One end of DNA to be sequenced is attached to anotherbead, with both beads being placed in optical traps. RNAP motion duringtranscription brings the beads in closer and their relative distancechanges, which can then be recorded at a single nucleotide resolution.The sequence is deduced based on the four readouts with loweredconcentrations of each of the four nucleotide types, similarly to theSanger method. Other high speed gene sequencers can be used.

In another embodiment, a spectrophotometer for nucleic acid measurementcan be used to determine the average concentrations of the nucleic acidsDNA or RNA present in a mixture, as well as their purity. To date, thereare two main approaches used by scientists to quantitate DNA or RNA.These are spectrophotometry and fluorescence tagging. Spectrophotometricanalysis is based on the principles that nucleic acids absorbultraviolet light in a specific pattern. In the case of DNA and RNA, asample that is exposed to ultraviolet light at a wavelength of 260nanometres (nm) will absorb that ultraviolet light. The resulting effectis that less light will strike the photodetector and this will produce ahigher optical density (OD). Raman spectroscopy involces scatteringlight photons. Essentially, most photons scatter following a patternknown as ‘Rayleigh scattering’, but about 1 in a million particlesscatter non-elastically, in the ‘Raman scattering’ pattern. Ramanspectroscopy is capable of identifying the radiation of those photons asit is absorbed and re-emitted by materials. And every material it comesinto contact with comes with its own unique ‘signature’. These effectsare created with a specific laser, and the precise pattern that isgenerated by these photons practically reveal the signature of whateverit comes into contact with, allowing scientists to identify even veryminute particles.

An open source spectrophotometer called ramanPi-Raman Spectrometer canbe used, the content of which is incorporated by reference. Thespectrometer portion uses the Crossed Czerny-Turner Configuration and ateach point in the optical system:

1. The laser emits a 532 nm (green) beam of light.

2. The 532 nm Pass Filter only allows the 532 nm (green) light to pass,and filters out anything else.

3. The Cube Beam Splitter passes half of the light on to the ObjectiveLens, and the other half into the Beam Dump.

4. The Objective Lens focuses the light down to a tiny point in thesample.

5. The light in the sample interacts with the molecules, and dependingon vibrations, bond angles, etc. the light is shifted from 532 nm(green) to other colors/frequencies.

6. Some of the shifted light and a lot of the original laser light isreflected back into the Objective Lens and is collimated back to theCube Beam Splitter.

7. The Cube Beam Splitter reflects half of the light to the FilterAssembly and half back into the laser.

8. The Filter Assembly contains two Edge Filters which block the 532 nm(green) laser light and allow the other colors to pass. Since this is alow cost system, two edge filters are used instead of one Notch Filter .. . and so two separate exposures are taken and the images are stacked.

9. The Vertical Aperture (slit) controls the amount of light that entersthe spectrometer section, and is a determining factor in spectralresolution.

10. The light from the slit is reflected off the Collimating Mirror onits way to the Diffraction

Grating.

11. The Diffraction Grating acts like a Prism and divides the light intoseparate colors. Since the light originated as 532 nm (green), and theshift is typically fairly minor, this light may be close to the originalcolor . . . but also may be red (lower frequency) or even blue (higherfrequency).

12. The light reflected from the Diffraction Grating is reflected by theImaging or Focusing Mirror onto the Detector Array.

13. The spectra derived from the above process is reflected by theImaging Mirror onto the CCD Array where it is captured by theraspberryPi for processing. One image is taken with the first EdgeFilter, then another exposure with the next Edge Filter and then somesoftware to stack the images is used together along with some signalprocessing and possibly multiple exposures to gain as much brightness aspossible so the computer can correctly analyze the spectra.

Gas chromatography-mass spectrometry (GC-MS) can be used to analyzemetabolites from biological samples. Compared with the typical GC-MSsystem, comprehensive two dimensional gas chromatography-time-of-flightmass spectrometry (GC×GC-TOF MS) is a more powerful analytical platform,with an order-of-magnitude increase in separation capacity, an increasein signal-to-noise ratio and dynamic range, and improvement of massspectral deconvolution and similarity matches. The GC×GC-TOF MSinstrument employs two capillary GC columns of different polaritiesconnected via a thermal modulator to achieve a high degree of separationof metabolites. Typically, the second column is short (0.5-2 m) andoperated at a higher temperature than the first column (10-60 m). Themetabolites coeluted from the first GC column are further separated inthe second column because of the difference in column temperature andstationary phase. The further separated metabolites are directed to atime-of-flight mass spectrometry system for detection.

One embodiment of the system applies pharmacogenomic information toselect the best medication and identify people who need an unusuallyhigh or low dose. This is in addition to clinical factors, such as apatient's age, weight, sex, and liver and kidney function.Pharmacogenomics (sometimes called pharmacogenetics) is focused onunderstanding how genes affect individual responses to medications andto help doctors select the cosmetic materials and dosages best suitedfor each person. Pharmacogenomics looks at variations in genes forproteins that influence cosmetic material responses. Such proteinsinclude a number of liver enzymes that convert medications into theiractive or inactive forms. Even small differences in the geneticsequences of these enzymes can have a big impact on a cosmeticmaterial's safety or effectiveness. One example involves a liver enzymeknown as CYP2D6. This enzyme acts on a quarter of all prescriptioncosmetic materials, including the painkiller codeine, which it convertsinto the cosmetic material's active form, morphine. The CYP2D6 geneexists in more than 160 different versions, many of which vary by only asingle difference in their DNA sequence, although some have largerchanges. The majority of these variants don't affect cosmetic materialresponses. Some people have hundreds or even thousands of copies of theCYP2D6 gene (typically, people have two copies of each gene). Those withextra copies of this gene manufacture an overabundance of CYP2D6 enzymemolecules and metabolize the cosmetic material very rapidly. As aresult, codeine may be converted to morphine so quickly and completelythat a standard dose of the cosmetic material can be an overdose. On theother end of the spectrum, some variants of CYP2D6 result in anonfunctional enzyme. People with these variants metabolize codeineslowly, if at all, so they might not experience much pain relief. Forthese people, doctors might prescribe a different type of pain reliever.Pharmacogenomic information can cover dosage guidance, possible sideeffects or differences in effectiveness for people with certain genomicvariations—can help doctors tailor their cosmetic material prescriptionsfor individual patients. The system applies pharmacogenomic data todevelop and market cosmetic materials for people with specific geneticprofiles. The system can identify the genetic basis for certain seriousside effects, cosmetic materials could be prescribed only to people whoare not at risk for them. As a result, potentially lifesavingmedications, which otherwise might be taken off the market because theypose a risk for some people, could still be available to those who couldbenefit from them. For example, a few cosmetic material and geneassociations are listed in the Appendix.

It will be recognized by the skilled artisan that while the computervisualization for cosmetic material interaction information retrievallogic 270 is shown to execute in a single host computing platform 202,the invention is not so limited and the computer visualization forcosmetic material interaction information retrieval logic 270 also canbe distributed in form across multiple different computing platforms.Further, the camera 220 and marshalling apparatus 230 can be locatedremotely from the host computing platform 202 whilst providing acquiredimagery to the host computing platform 210 over a computercommunications network, whether wireless or wirebound. Yet further,either or both of the cosmetic material image data store 250 and thecosmetic material interaction data store 260 can be remotely disposedfrom the host computing platform 202 and accessible over a computercommunications network, whether wireless or wirebound.

In general, database 260 includes information about cosmetic products,which may include their price, their availability, their attributes(e.g., color, coverage, viscosity, luminosity, sheen, sparkle, etc.),manufacturers, etc. Database 260 may also include information aboutpublic figures, such as celebrities. Such public figure information caninclude data about the public figure's skin tone, bone structure, faceshape, and cosmetic products that are used by the public figure.Database 260 may also include demo, review, and/or instructionalinformation, such as references to online videos, articles, pamphlets,etc., that can be disseminated to a user based on a recommend cosmeticproduct, and/or based on a matched public figure. Database 260 may alsoinclude advertising information, which can be disseminated to usersthrough system in any appropriate context or manner.

As noted, database 260 can include information about public figures,such as celebrities, such as cosmetic products and styles that are usedby public figures. As such, computer architecture 100 can be used tohelp a person to identify public figures that have skin and facialfeatures that are similar to their own skin and facial features, and toleverage knowledge of what cosmetic products the public figure uses—andhow the public figure uses those products—for cosmetic recommendations.Additionally or alternatively, computer architecture 100 can even beused to help a person not having skin tones and facial features similarto a desired public figure to duplicate that public figure's look ontheir own skin tones and facial features. As such, computer may adjustcolor recommendations to duplicate a public figure's look on the user'sskin tone and features.

In some embodiments, the system may be configured to simulateapplication of one or more cosmetic products to the user's face. Forexample, the system may visually present a generic image of a face, oreven a photographic capture of the user's face, and simulate what thegeneric image or the photograph of the user's face would look like withone or more cosmetic products applied thereto. The system may providefunctionality for adjusting the virtual application of each cosmeticproduct (e.g., order, quantity, location, etc.), for selectingsubstituting different products, for selecting different combinations ofproducts, etc.

In some embodiments, the system may be configured to instruct a user howto apply cosmetic products. For example, an example instruction imagevisually shows a user where and/or how to apply different cosmeticproducts. Such instruction image may guide a user through techniques foremphasizing certain facial features, for de-emphasizing certain facialfeatures, for achieving desired color or texture features, etc. Suchinstruction image may include the user's own face, or may be selectedfrom one or more generic models. When the system provides cosmeticrecommendations, the devices can provide rich interactive functionalityto the user for filtering and comparing cosmetic products. For example,the user may be enabled to filter products by price, manufacturer,public figure, attribute (e.g., color, coverage, etc.), availability,environmental friendliness, animal friendliness, toxicity, etc. Inanother example, a user may be enabled two visually compare two or moreproducts side-by-side, such as to compare color, texture, etc. Forexample, when a user is looking for a substitute of a remnant, thetesting device 104 may display the image that was captured of theremnant (or a derivation thereof) side-by-side with images of candidatereplacement products.

As indicated previously, database 260 may also include demo, review,and/or instructional information that can be disseminated to a userbased on a recommend cosmetic product, and/or based on a matched publicfigure. Such information may be disseminated to a user by way ofelectronic mail, SMS/MMS messaging, physical printouts, wirelesstransfer, communication with a corresponding mobile application, etc. Inaddition, the system may be configured to enable a user to purchaserecommended cosmetic products at the system, such as for home shipmentor in-store pickup.

The disclosed methods include measuring skin health-associated SNPs orother genetic markers in the biological sample obtained from the subjectand comparing that to a control or reference value. In some examples, asubject's genetic potential is determined in five areas of skin healthby analyzing one or more skin health-associated SNPs or other geneticmarkers associated with the five areas of skin health in a sampleobtained from the subject. The one or more areas of skin health caninclude assessing the following factors: collagen formation, sunprotection, antioxidant protection, glycation protection andinflammation control. Methods of isolating nucleic acid molecules from abiological sample are routine and known to those of ordinary skill inthe art, for example using PCR to amplify the molecules from the sample,or by using a commercially available kit to isolate DNA. Nucleic acidmolecules isolated from buccal swab samples or any other biologicalsample can be amplified using routine methods to form nucleic acidamplification products. Exemplary methods of isolating DNA and detectingSNPs associated with one or more skin conditions or disorders aredescribed below in the Molecular Methods Section.

a. Halyuronic Acid Rating

Numerous roles of HA in the body have been identified. It plays animportant role in the biological organism, as a mechanical support forthe cells of many tissues, such as the skin, tendons, muscles andcartilage. HA is involved in key biological processes, such as themoistening of tissues, and lubrication. It is also suspected of having arole in numerous physiological functions, such as adhesion, development,cell motility, cancer, angiogenesis, and wound healing. Due to theunique physical and biological properties of HA (includingviscoelasticity, biocompatibility, biodegradability), HA is employed ina wide range of current and developing applications withinophthalmology, rheumatology, drug delivery, wound healing and tissueengineering.

b. Collagen Rating

Collagen is a principal structural protein of the skin and plays a rolein skin firmness, fullness or plumpness and well as wrinkles. The speedof collagen synthesis and breakdown is influenced by a subject's geneticmakeup. Genes known to be involved in slowing the breakdown and/ordegradation of collagen fibers in skin can be collagen formationfactors. A higher score in the disclosed assay of collagen formationfactors indicates a more ideal genetic disposition for slowing thebreakdown of collagen. A lower score indicates a greater likelihood ofcollagen breakdown, an MMP-1 and collagen imbalance, a decrease intissue remodeling, ineffective wound healing and thus, the need for askincare and/or nutritional treatment to prevent, inhibit or reduce oneor more of these factors. A need for treating a collagen formationassociated condition can also be identified by the presence of one ormore of the following: prolonged skin redness; poor wound healing;accelerated aging; and/or skin laxity and/or sagging.

c. Sun Protection Rating

Ultraviolet (UV) exposure causes skin deterioration, premature skinaging, and a host of other profound changes to your skin. Exposure to UVlight from the sun accounts for 90% of the symptoms of early skin aging.A subject's genetic makeup influences the effect that UV exposure onskin. A higher score with the present assay indicates a greater naturalgenetic protection. A lower score indicates likelihood of increased UVfree radical damage, irregular cellular function, increasedmitochondrial damage, DNA structural damage and ineffectivemelanogenesis and thus, the need for a skincare and/or nutritionaltreatment to prevent, inhibit or reduce one or more of these factors. Aneed for treating a sun protection associated condition can also beidentified by the presence of one or more of the following: blemishesand redness; excess pigmentation, freckles and/or brown spots: skinthinning; fine lines; rough surface texture; enlarged pores; and/orredness/broken capillaries.

d. Antioxidant Protection Rating

The oxidation phenomenon caused by free radicals is recognized as one ofthe leading causes of skin aging. A primary factor in determining damagefrom free radicals is controlled by genes known to be associated withantioxidant activities. A higher score indicates an increased geneticadvantage for antioxidant protection. A lower score indicates likelihoodof heightened free-radical cellular destruction, premature cell death;increased mitochondrial damage; decreased antioxidant functioning,decreased quinone detoxification and thus, the need for a skincareand/or nutritional treatment to prevent, inhibit or reduce one or moreof these factors. A need for treating an antioxidant protectionassociated condition can also be identified by the presence of one ormore of the following: uneven skin tone, irregular pigmentation; roughskin texture; acne and rosacea; excess skin dryness or oiliness; and/oraccelerated aging and/or thinning of skin.

e. Glycation Protection Rating

Advanced Glycation End Products (AGEs) are the end result of aglucose-driven process known as glycation. Glycation is implicated inaccelerated skin aging, leading to wrinkling, dryness, sagging, andlaxity in your skin. A subject's score indicates the subject's geneticprotection against glycation: a higher score indicates a more optimalpredisposition. A lower score indicates likelihood of glucose/collagencross-linking: decreased skin elasticity; stiffened collagen fibers,weak dermal epidermal junctions; increased production of free radicals,and thus, the need for a skincare and/or nutritional treatment toprevent, inhibit or reduce one or more of these factors. A need fortreating a glycation protection associated condition can also beidentified by the presence of one or more of the following: heavywrinkles and/or skin folds; accelerated aging; sagging skin; crackingand thinning skin; and/or uneven skin texture.

f. Inflammation Rating

Inflammation is skin's first line of defense against foreign substanceslike bacteria and chemicals. However, excessive inflammation is one ofthe most common causes of early onset skin deterioration and aging. Asubject's genetic makeup play a role in the regulation of inflammation:a higher score indicates a greater capacity to reduce inflammation.

A lower score indicates possible irregular tissue healing, decreasedcellular defense, overactive inflammatory signaling, enhancedsensitivity, decreased efficacy of the detoxification process, increasedproduction of free radicals and thus, the need for a skincare and/ornutritional treatment to prevent, inhibit or reduce one or more of thesefactors. A need for treating an inflammation control factor associatedcondition can also be identified by the presence of one or more of thefollowing: skin redness; acne rosacea; rashes, swelling and/ordermatitis (eczema); accelerated aging; and/or enhanced sensitivity toforeign substances like bacteria and chemicals.

iii. Providing a Skin Profile to a Subject

Following the measurement of one or more SNPs associated with skinhealth, the results, findings, diagnoses, predictions and/or treatmentrecommendations can be provided to the subject. For example, theresults, findings, diagnoses, predictions and/or treatmentrecommendations can be recorded and communicated to technicians,physicians and/or patients or clients. In certain embodiments, computerscan be used to communicate such information to interested parties, suchas, clients, patients and/or the attending physicians. Based on themeasurement, the therapy or protocol administered to a subject can bestarted, modified not started or re-started (in the case of monitoringfor a reoccurrence of a particular skin condition/disorder).

In some examples, the output can provide a recommended therapeuticregimen or skin care protocol. In some examples, the test may includedetermination of other clinical information.

In some embodiments, the disclosed methods include one or more of thefollowing depending on the subject's skin profile: a) prescribing orrecommending a protocol or treatment regimen for the subject if thesubject's determined profile is considered to be high or medium risk,sub-optimal or deficient in one or more areas of skin health; b) notprescribing or recommending a protocol or treatment regimen for thesubject if the subject's determined skin profile is considered to beoptimal in the evaluated skin areas; c) administering a protocol ortreatment to the subject if the subject's determined diagnosis orprofile is considered to be high or medium risk or sub-optimal ordeficient in one or more areas of skin health or appearance; d) notadministering a protocol or treatment regimen to the subject if thesubject's determined skin profile is considered to be optimal in theevaluated skin areas. In an alternative embodiment, the method caninclude recommending one or more of a)-d).

In addition to DNA testing for skin tone, the present inventor alsocontemplates camera based skin tone detection. In this embodiment, thesystem comprises an act of capturing a face scan. Act can includecapturing a photographic image, spectrophotometer scan, etc. of a user'sface using one or more of the sensing devices 105 a. In capturing theface scan, the system may provide for predefined and controlled lightingconditions, and/or may adjust the white balance or other colorparameters of a captured photographic image. The system also comprisesan act of determining a skin tone. The system can include determining,from the face scan, a skin tone of the user's face. For example, thesystem may use software algorithms and analysis module to ascertain theskin tone, or the testing device may upload the face scan to the serversfor processing.

The method includes identifying cosmetic products) based on the skintone. For example, the system includes identifying, based on the skintone of the user's face, one or more cosmetic products that arerecommended for the user. For example, the system may identify cosmeticproducts in database 260 that are recommended for the user based on theskin tone. Such recommendation may be made based on identifying one ormore cosmetic products having a color that matches the user's skin tone,or having a color that compliments the user's skin tone. Theidentification of products may be based on price, brand/manufacturer,product line, public figure, etc.

The system provides a cosmetic recommendation including the identifiedcosmetic product(s). The system can include providing a cosmeticrecommendation to the user, the cosmetic recommendation including theone or more cosmetic products that are recommended for the user based onthe skin tone of the user's face. For example, the system may formulatea cosmetic recommendation. The system can send then communicate thecosmetic recommendation to the user. Testing device 104 can communicatethe cosmetic recommendation using the output module 106 and outputdevices 106 a visually, with a printout, or electronically to one ormore of a smartphone, a tablet computer, a desktop computer, or a laptopcomputer.

Any skin surface can be treated using the methods provided herein. By“skin surface” is intended the stratum corneum, epidermis, dermis or anyother layer of the skin thereof. Skin surfaces that can be treatedinclude, but are not limited to face, scalp, neck, chest, back, torso,arms, legs, hands or feet including periorbits, lips, cheeks, nasolabialfolds, forehead, chin, neck, upper lip rhytides, or any combinationthereof. The skin of any facial surface can be treated using the methodsprovided herein. The method can be applied to any facial or scalp areaand/or to any body surface area, with other immediate areas ofapplication being the chest, neck and body. More than one skin surfacecan be treated during the same treatment period.

Improving skin quality includes reversing, slowing the progression of,supporting the healthy function of or preventing skin changes associatedwith natural or innate aging or other biological or disease effects. Asused herein, “prevent” and variations thereof refer to any degree ofdelaying the onset of skin changes. For example, improving skin qualityincludes the reversal, slowing the progression of, or prevention of skinchanges associated with sun damage or photo aging, skin changesassociated with exposure to sunlight or other forms of actinic radiation(for example, UV radiation and tanning booths). As another example,improving skin quality also can include reversing, slowing theprogression of, or preventing skin changes resulting from extrinsicfactors, including, but not limited to, radiation, air pollution, sun,UV rays, wind, cold, dampness, heat, chemicals, smoke, cigarettesmoking, and combinations thereof. Improving skin quality also caninclude reversing, preventing or reducing scarring the can result, forexample, from certain skin conditions (for example, acne), infections(for example, leishmaniasis), or injury (for example, abrasions,punctures, lacerations, or surgical wounds). Improvements to the skincan also include at least one of the following: reducing red, brown orany other abnormal pigment making facial lines appear less noticeable,making facial lines and/or wrinkles feel plumped, improving theappearance of suborbital lines and/or periorbital lines, improving theappearance of crow's feet, reducing and/or diminishing the appearance ofwrinkles, particularly facial wrinkles on the cheeks, forehead (forexample, perpendicular wrinkles between eyes, horizontal wrinkles abovethe eyes), and/or around the mouth, and particularly deep wrinkles,folds, or creases, improving skin suppleness smoothness texture andtone, reducing and/or eliminating fine and/or deep lines, folds andcreases, and smoothing skin. Skin changes treatable by practicing themethods and using the assays disclosed herein include, for example,wrinkles (including, but not limited to, human facial wrinkles),creases, furrows, folds and fine lines, deepening of skin lines,thinning of skin, reduced scarring, yellowing, browning or reddening ofthe skin, mottling, hyperpigmentation, appearance of pigmented and/ornon-pigmented age spots, leatheriness, loss of elasticity, loss ofrecoilability, loss of collagen fibers, abnormal changes in the elasticfibers, deterioration of small blood vessels of the dermis, formation ofsolar increased visible vasculature on the skin surface, inflammationincluding redness, dryness or irritation of the skin or any other skinabnormality or combinations thereof.

Improving skin quality includes decreasing, reducing, and/or minimizingone or more of the skin changes discussed above. Improving skin qualitycan result in the skin having a more youthful and healthy appearance.Improving skin quality can result in the skin having a smoother,hydrated (less dry), or less scaly appearance. For example, in certainembodiments, improving skin quality can include a reduction inroughness, dryness, irritation or scaliness. Improving skin qualityincludes the effacement and improvement of lines and wrinkles,improvement in turgor, and tonicity, with the observed desired effectsof lifting and tightening.

The textural qualities of the skin can be improved, including softness,suppleness, and smoothness, leading to enhancement of luster, clarityand brightness. Additional and important qualities of the skin that canbe subjectively and objectively measured include, but are not limited toskin laxity, or conversely skin tightness, and the presence and degreeof textural fine lines and coarser lines within the skin.

These are the same qualities by which the external aspects of appearance(for example, aging of skin) are judged. Improvement in these qualitiesby the method of treatment and kits disclosed herein result in a benefitbased on visual judgment of appearance. Changing a quality of the skinby the methods disclosed herein lessens the appearance of aging of theskin.

Desired benefits may include not only physiologic benefit to the skin,but therapeutic and pharmacologic benefits, such as possible malignancyprevention and treatment. Benefits may also include acne treatment andsuppression, by including compositions which suppress sebaceousglandular activity, enhance bacterial suppression, or enhance retinoiddelivery into the skin.

Exemplary Compositions that can be customized to skin treatmentincludes:

i. Antioxidant Cleanser

In some examples, an antioxidant cleanser is applied topically to a skinsurface as needed, such as to prevent, reduce, or inhibit one or moresigns or symptoms associated with high or medium risk or sub-normal ordeficient skin health factors. In one example, the antioxidant cleansercomprises: sodium lauryl glucose carboxylate; lauryl glucoside;coco-glucoside; cocamidopropyl betaine; glyceryl oleate; glycerin;caprylyl glycol; citrus grandis (grapefruit) peel oil; panthenol;Solanum lycopersicum (tomato) extract; citrus aurantium bergamia(bergamot) fruit oil; Thymus vulgaris (thyme) extract; algae extract;aloe barbadensis leaf; and citrus medica limonum (lemon) peel oil.

ii. Balancing Toner

In some examples, a balancing toner is applied topically to a skinsurface as needed, such as to prevent, reduce, or inhibit one or moresigns or symptoms associated with high or medium risk or sub-normal ordeficient skin health factors. In one example, the balancing tonercomprises: methyl gluceth-20; glycerin; caprylyl glycol; sodium PGA;panthenol; citrus grandis (grapefruit) peel oil; Thymus vulgaris (thymeextract); citrus aurantium amara (bitter orange) extract; hamamelisvirginiana (witch hazel) bark/leaf/twig extract; glycine soja (soybean)seed extract; Solanum lycopersicum (tomato) extract; citrus aurantiumbergamia (bergamot) fruit oil; aloe barbadensis leaf; ascorbic acid;tocopheryl acetate; retinyl palmitate; and bioflavonoids.

iii. Wrinkle Treatment Serum

In some examples, a wrinkle treatment serum is applied topically to askin surface as needed, such as to prevent, reduce, or inhibit one ormore signs or symptoms associated with high or medium risk or sub-normalor deficient skin health factors. In one example, the wrinkle treatmentserum comprises: acetyl octapeptide-3 (SNAP-8); capryly glycol;glycerin; palmitoyl oligopeptide, palmitoyl tetrapeptide-7 (also knownas Matrixyl-300); hyaluronic acid; Solanum lycopersicum (tomato)extract; Thymus vulgaris (thyme) extract; aloe barbadensis leaf;leontopodium alpinum (edelweiss) flower/leaf extract; glycine soja(soybean) seed extract; citrus grandis (grapefruit) peel oil; andallantoin.

iv. Vitamin C Treatment Serum

In some examples, a vitamin C treatment serum is applied topically to askin surface as needed, such as to prevent, reduce, or inhibit one ormore signs or symptoms associated with high or medium risk or sub-normalor deficient skin health factors. In one example, the vitamin Ctreatment serum comprises: cyclopentasiloxane, dimethicone crosspolymer,cyclomethicone; sodium ascorbyl phosphate; idebenone; caprylyl glycol;citrus grandis (grapefruit) peel oil; magnesium ascorbyl phosphate;citrus aurantium dulcis (orange) peel oil; aloe barbadensis leaf;retinyl palmitate; and tocopherol.

v. Calming Treatment Serum

In some examples, calming treatment serum is applied topically to a skinsurface as needed, such as to prevent, reduce, or inhibit one or moresigns or symptoms associated with high or medium risk or sub-normal ordeficient skin health factors. In one example, the calming treatmentserum comprises: glycerin; sodium cocoyl amino acids, sarcosine,potassium aspartate, magnesium aspartate, caprylyl glycol; hyaluronicacid; caprylic/capric triglyceride; citrus grandis (grapefruit) peeloil; glycine soja (soybean) seed extract; Thymus vulgaris (thyme)extract; arnica montana flower extract; Solanum lycopersicum (tomato)extract; leontopodium alpinum (edelweiss) flower/leaf extract; alebarbadensis leaf; and epilobium angustifolium (canadian willow) extract.

vi. Hyaluronic Moisture Treatment Serum

In some examples, hyaluronic moisture treatment serum is appliedtopically to a skin surface as needed, such as to prevent, reduce, orinhibit one or more signs or symptoms associated with high or mediumrisk or sub-normal or deficient skin health factors. In one example, thehyaluronic moisture treatment serum comprises: hyaluronic acid; sodiumPGA; caprylyl glycol; glycerin; panthenol; avena sative (oat) kernelextract; Thymus vulgaris (thyme) extract; saccharomyces/silicon ferment,saccharomyces/copper ferment, saccharomyces/iron ferment,saccharomyces/zinc ferment; aloe barbadensis leaf; leontopodium alpinumflower/leaf extract; and allantoin.

vii. Antioxidant Moisturizer

In some examples, an antioxidant moisture is applied topically to a skinsurface as needed, such as to prevent, reduce, or inhibit one or moresigns or symptoms associated with high or medium risk or sub-normal ordeficient skin health factors. In one example, the antioxidant moisturecomprises: polyacrylamide; glycerin; sorbitol, caprylic/caprictriglyceride, squalene, cyclomethicone, caprylyl glycol, hyaluronicacid, glycoproteins, citrus grandis, Thymus vulgaris (thyme) extract,thioctic acid, Solanum lycopersicum (Tomato) extract, camellia oleifera(green tea) leaf extract, Oryza sativa (rice) bran oil, tocopherylacetate, aloe barbadensis leaf, ubiquinone, and glycine soja (soybean)seed extract

viii. Collagen Composition

In some examples, a subject determined to have sub-normal or deficientlevels of collagen protection factors, is administered a collagendefense composition to reduce, inhibit, and/or prevent one or more signsassociated with high or medium risk or sub-normal or deficient levels ofcollagen protection factors. In some examples, the collagen defensecomposition is in tablet/capsule form and is administered to the subjecttwice daily and includes the following: Choline (as Choline-StabilizedOrthosilicic Acid), and Silicon (as Choline-Stabilized OrthosilicicAcid).

ix. Sun Composition

In some examples, a subject determined to have sub-normal or deficientlevels of sun protection factors, is administered a sun defensecomposition to reduce, inhibit, and/or prevent one or more signsassociated with high or medium risk or sub-normal or deficient levels ofsun protection factors. In some examples, a sun defense compositionsincludes trans-resveratrol and quercetin. In some examples, the sundefense composition is in tablet/capsule form and is administered to thesubject twice daily and includes the following: Trans-Resveratrol(Polygonum Cuspidatum), Quercetin Dihydrate, Lecithin, MicrocrystallineCellulose, Dicalcum Phosphate, Silicon Dioxide, Vegetable Stearate

x. Antioxidant Composition

In some examples, a subject determined to have sub-normal or deficientlevels of antioxidant protection factors, is administered an antioxidantdefense composition to reduce, inhibit, and/or prevent one or more signsassociated with high or medium risk or sub-normal or deficient levels ofantioxidant protection factors. In some examples, the antioxidantdefense composition is in tablet/capsule form and is administered to thesubject three times daily and includes the following: Vitamin A (asNatural Mixed Carotenoids Complex), Alpha Carotene 2.5, Beta Carotene,Acerola (Malpighia Glabra), High Gamma Mixed Tocopherols, Grape SeedExtract (Wis Vinifera), Curcumin C3 Complex® (Curcumin, BisdemethoxyCurcumin, Demethoxy Curcumin), Garlic (Allium Sativum), Tocotrienols(from Annatto Bean), Ginkgo Biloba, Quercetin, Rutin, Clove (SyzygiumAromaticum), Allspice (Pimenta Dioca), Sweet Basil (Ocimum Basilicum),Sage (Salvia Officinalis), Rosemary (Rosemarinus Officinalus), PolygonumCuspidatum (50% Trans-Resveratrol), Lutein (Tagetes Erecta L) (MarigoldLutein Esters), Lycopene, Microcrystalline Cellulose, Silicon Dioxide,Stearates (Vegetable Source).

xi. Glycation Composition

In some examples, a subject determined to have sub-normal or deficientlevels of glycation protection factors, is administered a glycationdefense composition to reduce, inhibit, and/or prevent one or more signsassociated with high or medium risk or sub-normal or deficient levels ofglycation protection factors. Excess sugar in the body is a primarycause of premature skin aging because of its role in a process calledglycation. Glycation occurs when blood sugar binds to collagen andelastin fibers, essentially “caramelizing” or hardening skin. Glycatedskin results in skin laxity, cracking, thinning, redness and inabilityto self-repair. In some examples, a glycation defense composition isadministered to the subject wherein the composition comprises herbs,polyphenols and antioxidants to sugar levels and protect againstglycation. In some examples, the glycation defense composition is intablet/capsule form and is administered to the subject twice daily andincludes Salacia (Salacia Oblonga), Fennugreek (TrigonellaFoenum-Graecum), American Ginseng (Panax Quinquefolius), Gymnema(Gymnema Sylvestre), Banaba (Langerstroemia Spp.), Kudzu (Pueraraialobata), Cinnamon (Cinnamomum Spp.), Microcrystalline Cellulose, andVegetable Stearate.

xii. Inflammation Composition

In some examples, a subject determined to have high or medium risk orsub-normal or deficient levels of inflammation protection factors, isadministered an inflammation defense composition to reduce, inhibit,and/or prevent one or more signs associated with skin inflammation suchas skin sensitivity, redness, irritation, acne, rosacea and eczema. Insome examples, an inflammation defense composition comprises n*Zimes®Proprietary Blend (Protease 6.0, Protease 4.5, Trypsin 1:150),Serrazimes®, Chymotrypsin, Turmeric (Curcuma Longa), Boswellia(Boswellia Serrata), Ginger (Zingiber Offinale), Ouercetin, Rutin,Rosemary Extract (Rosemarinus Officinalis), Microcrystalline Cellulose,Silicon Dioxide, Vegetable Stearate. This inflammation defensecomposition is administered in tablet/capsule form, twice daily.

Providing a cosmetic recommendation may include visually simulatingapplication of at least one cosmetic product to the scan of the user'sface. Providing a cosmetic recommendation may also include providing atleast one review of a cosmetic product, which may include sending theuser a Uniform Resource Locator (URL) to an Internet video, review,publication, etc. In some embodiments, the cosmetic recommendation islimited by one or more filter criteria that are received from the user,such as product attributes (e.g., coverage, viscosity, luminosity,etc.), price, brand, celebrity, etc. In some embodiments, methodincludes identifying, from a public figure database (e.g., withindatabase 260), at least one public figure having a skin tone that is thesame as, or within a predefined color threshold to, the skin tone of theuser's face. In such embodiments, the identification of cosmeticproducts that are recommended for the user comprises identifying, fromthe public figure database, one or more cosmetic products that are usedby the public figure. In some embodiments, method includes receiving anidentity of a public figure (e.g., from the user), and then determining,from a public figure database, a skin tone of the public figure and oneor more cosmetic products that are used by the public figure. Based onthis information, a color difference between the skin tone of the publicfigure and the skin tone of the user is determined. Then, therecommended cosmetic products include a color adjustment that allows theuser to use products that are similar to the public figure's, but thatwork with the user's skin tone based on matching DNA characteristics orvisual identification through a camera, among others. For example:

-   -   Redheads with fair to medium skin tones like Susan Sarandon,        Nicole Kidman, and Julianne Moore tend to wear corals, salmon,        browns, ambers, bronze, and other earth tones.    -   Blondes with fair skin to medium skin tones like Gwyneth        Paltrow, Emma Stone, and Kirsten Dunst favor a range of pink        shades.    -   Brunettes with fair to medium skin tones like Julia Roberts and        Jennifer Garner are often seen in light rose and soft red        shades.    -   Women with dark brown hair and fair to medium skin tones like        Demi Moore, Sandra Bullock, and Penelope Cruz wear more vivid        shades of rose and cherry.    -   Black hair and deeper skin tones such as Halle Berry and Zoe        Saldana or Oprah Winfrey wear soft natural tones such as nude        pinks, soft browns, and corals.

One embodiment allows selection of a color lipstick family from the DNAdata. The customer can enter a specific lipstick number, or choose acolor family, then choose a color from the family. The active colorpalette will consist of individual palettes that contain that lipstick.The customer can also enter a specific look or a selection of lipstickfrom a color family. If the lipstick is also in the paletterecommendation based on skin tone, the color is put first in the list,and (expert fit) is added to the name.

The system can select color for the following exemplary cosmeticcomponents:

Primer comes in formulas to suit individual skin conditions. Most aremeant to reduce the appearance of pore size, prolong the wear of makeup,and allow for a smoother application of makeup. Primers are appliedbefore foundation or eyeshadows depending on where the primer is to beapplied.

Lipstick, lip gloss, lip liner, lip plumper, lip balm, lip stain, lipconditioner, lip primer, lip boosters, and lip butters: Lipsticks areintended to add color and texture to the lips and often come in a widerange of colors, as well as finishes such as matte, satin and lustre.Lip stains have a water or gel base and may contain alcohol to help theproduct stay on leaving a matte look. They temporarily saturate the lipswith a dye. Usually designed to be waterproof, the product may come withan applicator brush, rollerball, or could be applied with a finger. Lipglosses are intended to add shine to the lips and may add a tint ofcolor, as well as being scented or flavored for a pop of fun. Lip balmsare most often used to moisturize, tint and protect the lips. They oftencontain SPF protection depending on what brand it is bought from.

Concealer makeup covers imperfections of the skin. Concealer is oftenused for any extra coverage needed to cover blemishes, undereye circles,and other imperfections. Concealer is often thicker and more solid thanfoundation, and provides longer lasting, more detailed coverage. Someformulations are meant only for the eye or only for the face. Thisproduct can also be used for contouring the face like ones nose,cheekbones, and jaw line to add a more defined look to the total face.

Foundation is used to smooth out the face and cover spots, acne andblemishes or uneven skin coloration. Usually a liquid, cream, or powder,as well as most recently a light and fluffy mousse. Foundation providescoverage from sheer to matt to dewey or full. Foundation primer can beapplied before or after foundation to obtain a smoother finish. Someprimers come in powder or liquid form to be applied before foundation asa base, while other primers come as a spray to be applied after thefoundation to set the make-up and help it last longer throughout theday.

Face powder sets the foundation, giving it a matte finish, and toconceal small flaws or blemishes and can also be used to bake thefoundation, so it stays on longer. Tinted face powders may be worn aloneas a light foundation so that the full face does not look as caked up asit could.

Rouge, blush or blusher is cheek coloring to bring out the color in thecheeks and make the cheekbones appear more defined. Rouge comes inpowder, cream, and liquid forms. Different blushes compliment differentskin tones, however there is a blush for most skin tones.

Contour powder/creams are used to define the face. They can give theillusion of a slimmer face or to modify a face shape in other desiredways. Usually a few shades darker than one's own skin tone and matte infinish, contour products create the illusion of depth. A darker tonedfoundation/concealer can be used instead of contour products for a morenatural look.

Highlight, used to draw attention to the high points of the face as wellas to add glow, comes in liquid, cream, and powder forms. It oftencontains a substance to provide shimmer. A lighter tonedfoundation/concealer can be used instead of highlight to create a morenatural look and warm feel.

Bronzer gives skin a bit of color by adding a golden or bronze glow andhighlighting the cheekbones, as well as being used for contouring.Bronzer is considered to be more of a natural look and can be used foran everyday wear. Bronzer enhances the color of the face while addingmore of a shimmery look. It comes in either matte, semi matte/satin, orshimmer finishes.

Mascara is used to darken, lengthen, thicken, or draw attention to theeyelashes. It is available in natural colors such as brown and black,but also comes in bolder colors such as blue, pink, or purple. Somemascaras include glitter flecks. There are many formulas, includingwaterproof versions for those prone to allergies or sudden tears. It isoften used after an eyelash curler and mascara primer. Many mascarashave components to help lashes appear longer and thicker.

Eyeliner is used to enhance and elongate the size of the eye or to add acertain depth to the eye to create a certain look. For example, usingwhite eyeliner on the waterline and inner corners of the eye helps tomake the eyes look bigger and more awake.

Eyebrow pencils, creams, waxes, gels and powders are used to color, fillin and define the brows.

Nail polish is used to color the fingernails and toenails. Transparent,colorless versions may strengthen nails or as a top or base coat toprotect the nail or polish.

Setting spray is used as the last step in the process of applyingmakeup. It keeps applied makeup intact for long periods. An alternativeto setting spray is setting powder, which may be either pigmented ortranslucent. Both of these products claim to keep makeup from absorbinginto the skin or melting off.

False eyelashes are frequently used when extravagant and exaggeratedeyelashes are desired. Their basic design usually consists of human hairor synthetic materials attached to a thin cloth-like band, which isapplied with an eyelash glue to the lashline. Designs vary from short,natural-looking lashes to extremely long, wispy, rainbow-colored lashes.Rhinestones, gems, and even feathers and lace occur on some falseeyelash designs.

The system enables a medical model that separates patients intodifferent groups—with beautifying decisions, practices, interventionsand/or products being tailored to the individual user based on theirpredicted response or risk of skin disease from an ex vivo sample suchas a saliva sample or buccal swab provided by the individual prior totesting.

One embodiment identifies profilaggrin gene and protein. A profilaggringene comprises multiple filaggrin repeats, usually 10, 11 or 12 repeats.The filaggrin repeats are typically of the same length (972 bp, 324amino acids in humans) as each other, although this is less typical offilaggrin repeats at the 5′- and 3′-ends of the mRNA. The filaggrinrepeats may display considerable sequence variation, typically of from0-50%, more typically of from 2-30%, yet more typically of from 10-15%,between repeats on the same allele and between different alleles.Usually variations are attributable to a single-base change but may alsoinvolve a change in charge (Gan et al (1990) Biochemistry, 29,9432-9440). A consensus amino acid sequence map of a human filaggrinrepeat is known (Gan et al (1990) Biochemistry, 29, 9432-9440) andpreferably a filaggrin repeat will have at least 50%, more preferably atleast 75%, more preferably 90%, yet more preferably at least 95%sequence identity to that consensus sequence or a variant of theconsensus sequence shown in Gan et al (1990, Biochemistry, 29,9432-9440). Normally the amino acid sequences encoding the amino andcarboxy termini are more conserved, as are the 5′ and 3′ DNA sequencesflanking the coding portions of the gene (Presland et al (1992) J BiolChem, 267(33), 23772-23781). The presence of different profilaggrinalleles in the genome of an individual can be identified by methods wellknown in the art for distinguishing between macromolecules withdivergent structures. The term “allele” as used herein with respect toprofilaggrin refers to any profilaggrin gene comprising a polymorphism.In a preferred embodiment the term “allele” with respect to profilaggrinrefers to a profilaggrin gene identifiable by the number of filaggrinrepeats it encodes. However, the skilled person will appreciate thatmany other polymorphisms of the profilaggrin gene are possible and allprofilaggrin alleles are included within the scope of the invention. Forexample, the different phenotypes observed between individuals havingprofilaggrin alleles encoding profilaggrin with 10, 11 or 12 filaggrinrepeats may be a direct result of the differences in production offilaggrin. However, the skilled person will appreciate that the numberof filaggrin repeats may instead be a ‘marker’ for some other sequencepolymorphism in the different profilaggrin alleles, or in another genewithin the epidermal differentiation complex. Thus the phenotype may notbe directly related to the number of filaggrin repeats present. Thus itwill be appreciated that methods described herein will be suitable toidentify differences between any profilaggrin alleles and that theinvention is not restricted to polymorphism in respect of the number offilaggrin repeats.

Typically an allele may be identified at the polynucleotide level, suchas by analysis of genomic DNA or mRNA. The skilled person is well awareof methods for determining the presence or absence of differentpolynucleotides. Methods known for determining the presence or absenceof particular RNA sequences include northern blots, reversetranscription and PCR (RT-PCR) and ribonuclease protection assays(Sambrook and Russell, (2001) Molecular Cloning: A Laboratory Manual.3rd edition, Cold Spring Harbour Laboratory Press, New York, USA).Methods known for determining the presence or absence of particular DNAsequences include sequencing, Southern blots, PCR amplification ofgenomic DNA and analysis of restriction fragment length polymorphisms(RFLPs). See Sambrook and Russell (2001, Molecular Cloning: A LaboratoryManual. 3rd edition, Cold Spring Harbour Laboratory Press, New York,USA), Innis et al, (1995, PCR Strategies, Academic Press, Inc.: NY);Dieffenbach et al (1995, PCR Primer: A Laboratory Manual, New York: ColdSpring Harbor Press). DNA sequence analysis may also be achieved bydetecting alteration in electrophoretic mobility of DNA fragments ingels with or without denaturing agents. Differences can also bevisualized by high resolution gel electrophoresis or distinguishedaccording to differences in DNA sequence melting points. See, e.g.,Myers et al (1982, Science, 230, 1242). Methods for detecting thepresence of specific sequences include detection techniques such asfluorescence-based detection methods, immune-based assays such as RIA,antibody staining such as Western blot analysis or in situhybridization, using appropriately labeled probe.

Sequences useful for constructing probes suitable for use in detectingthe presence of a sequence of interest include any nucleic acid sequencehaving at least about 50%, preferably at least 70%, more preferably atleast 80% or greater sequence identity or homology with the sequence ofa known profilaggrin gene or fragment thereof by a Blast search.“Percent (%) sequence identity” or “percent (%) sequence homology” isdefined as the percentage of nucleic acid residues in a candidatesequence that are identical with the nucleic acid residues of thesequence of interest, after aligning the sequences and introducing gaps,if necessary to achieve maximum percent sequence identity, and notconsidering any conservative substitutions as part of the sequenceidentity. Methods for performing sequence alignment and determiningsequence identity are known in the art, may be performed without undueexperimentation, and calculations of % identity values may be obtainedfor example, using available computer programs such as WU-BLAST-2(Altschul et al, 1996, Methods in Enzymology 266,460-480). One mayoptionally perform the alignment using set default parameters in thecomputer software program (Blast search, MacVector and Vector NTI).Based upon the restriction map of a particular allele, a banding patterncan be predicted when the Southern blot is hybridized with a probe whichrecognizes the sequence of interest. The level of stringency ofhybridization used can vary depending upon the level of sensitivitydesired, a particular probe characteristic, such as probe length and/orannealing temperature, or degree of homology between probe sequence andsequence of interest. Therefore, considerations of sensitivity andspecificity will determine stringency of hybridization required for aparticular assay.

“Stringency” of hybridization reactions is readily determinable by oneof ordinary skill in the art, and generally is an empirical calculationdependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperatures. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature that can be used. For additional details and explanation ofstringency of hybridization reactions, see Ausubel et al (1995, CurrentProtocols in Molecular Biology, Wiley Interscience Publishers) orProtocols Online (URL: www.protocol-online.net/molbio/index.htm).

“Stringent conditions” or “high-stringency”, as defined herein, may beidentified by those that: (1) use low ionic strength and hightemperature for washing, for example 0.1×SSC, 0.2% SDS at 65-70° C.

“Moderately-stringent conditions” may be identified as described bySambrook and Russell (2001, Molecular Cloning: A Laboratory Manual, 3rdedition), and include the use of washing solution and hybridisationconditions (e.g. temperature, ionic strength, and % SDS) less stringentthat those described above. An example of moderately stringentconditions is 0.2×SSC, 0.1% SDS at 58-65° C. The skilled artisan willrecognise how to adjust temperature, ionic strength, etc. as necessaryto accommodate factors such as probe length, degree of homology betweenprobe and target site and the like. Therefore, in addition to thesequence of interest, it is contemplated that additional or alternativeprobe sequences which vary from that of the sequence of interest willalso be useful in screening for the sequence of interest.

In a preferred embodiment profilaggrin alleles are identified by thenumber of filaggrin repeats present. Thus typically the method ofidentifying the profilaggrin alleles present in the genome of anindividual comprises determining whether the alleles present have 10, 11or 12 filaggrin repeats.

In one preferred embodiment allele identification is performed usingPCR. Forward and reverse primers are prepared using techniques wellknown in the art and comprise a sequence based on an upstream region anda downstream region, respectively, relative to the sequence of theprofilaggrin gene coding sequence encoding polymorphic filaggrinrepeats. Preferably the upstream and downstream regions chosen fordesign of primers will be substantially conserved between differentalleles. “Substantially conserved” includes within its meaning sequenceshaving at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 100% sequenceidentity. Thus primers can be designed for binding to similar butnon-identical sequences, for example by using degenerate primers or byincluding nucleotides that have a reduced specificity for the purposesof complementarity, such as inosine, within the primer. Preferably one,or more preferably both, of the forward and reverse primers are 100%identical to the upstream and/or downstream regions of each profilaggrinallele.

The PCR reaction is performed in order to amplify DNA obtained from thebiological material from the sample taken from the individual. In oneembodiment the DNA is genomic DNA extracted from the biologicalmaterial. In another embodiment the DNA is cDNA which has been reversetranscribed from RNA, typically mRNA, which RNA has been extracted fromthe biological material. Methods for extracting genomic DNA, methods forextracting RNA, methods for extracting mRNA and methods for reversetranscription of RNA are well known in the art, for example see Sambrookand Russell (2001, Molecular Cloning: A Laboratory Manual. 3rd edition,Cold Spring Harbour Laboratory Press, New York, USA).

In a preferred embodiment the DNA is genomic DNA and the sample is asaliva sample or buccal swab. Methods for extracting DNA from salivasamples and buccal swabs are known in the art (Schie and Wilson (1997)Journal of Immunological Methods, 208, 91-101).

The PCR reaction can be performed under conditions well known in the artor as suggested by the manufacturer of a commercially available PCR kit.For example, amplification may be performed using from 0.1 to 30 μg/mlDNA substrate. Amplification may be performed using from 2 μM to 2 mMdNTPs. Amplification may be performed using from 2 μM to 2 mM forwardand reverse primers. Amplification may be performed using and from 17 μMto 170 mM Mg2+. In a preferred embodiment amplification is performedusing about 200 μM dNTPs. In a preferred embodiment amplification isperformed using about 200 μM forward and reverse primers. In a preferredembodiment amplification is performed using about 1.7 mM Mg2+. By“about” is meant that the concentration used varies by no more than 50%,25%, 10% or 5% from the concentration stated. Most preferably the PCRreaction is performed essentially as described in the exemplifiedmethods below.

PCR products can then be analysed by any suitable method. Typically thePCR products are analysed by size fractionation, usually using gelelectrophoresis performed in accordance with techniques well known inthe art (see Sambrook and Russell (2001) Molecular Cloning: A LaboratoryManual. 3rd edition, Cold Spring Harbour Laboratory Press, New York,USA). Most preferably the PCR products are analysed essentially asdescribed in the exemplified methods below.

Other methods suitable for identifying the profilaggrin alleles presentin the genome of an individual include allele specific hybridisation;allele specific oligonucleotide hybridisation; and primer specificextension.

Allele specific hybridization uses probes overlapping a region of atleast one profilaggrin allele and having about 5, 10, 20, 25 or 30nucleotides around a polymorphic region. In a preferred embodiment,several probes capable of hybridizing specifically to other profilaggrinalleles are attached to a solid phase support, e.g. a “chip,” (which canhold up to about 250,000 oligonucleotides). Oligonucleotides can bebound to a solid support by a variety of processes, includinglithography. Mutation detection analysis using these chips comprisingoligonucleotides, also terms “DNA probe arrays” is described e.g., inCronin et al (1996, Human Mutation 7, 244). In one embodiment, a chipcomprises all the allelic variants of at least one polymorphic region ofa profilaggrin gene. The solid phase support is then contacted with atest nucleic acid and hybridization to the specific probes is detected.Accordingly, the identity of numerous allelic variants of one or moregenes can be identified in a simple hybridization experiment.

These techniques may also comprise the step of amplifying the nucleicacid before analysis. Amplification techniques are known to those ofskill in the art and include, but are not limited to cloning, polymerasechain reaction (PCR), polymerase chain reaction of specific alleles(ASA), ligase chain region (LCR), nested polymerase chain reaction, selfsustained sequence replication (Guatelli et al (1990) Proc Natl Acad SciUSA 87, 1874-1878), transcriptional amplification system (Kwoh et al(1989) Proc Natl Acad Sci USA 86, 1173-1177), and Q-Beta Replicase(Lizardi (1988) Bio/Technology 6, 1197).

Amplification products may be assayed in a variety of ways, includingsize analysis, restriction digestion followed by size analysis,detecting specific tagged oligonucleotide primers in the reactionproducts, allele-specific oligonucleotide (ASO) hybridization, allelespecific 5′ exonuclease detection, sequencing, hybridization % and thelike.

In a merely illustrative embodiment a method of identifying profilaggrinalleles includes the steps of (i) isolating nucleic acid (e.g., genomic,RNA or both) from the cells of a sample collected from an individual(ii) contacting the nucleic acid sample with one or more primers whichspecifically hybridize 5′ and 3′ to at least one polymorphism in theprofilaggrin allele under conditions such that hybridization andamplification of the polymorphic region of the allele occurs, and (iii)detecting the amplification product. These detection schemes areespecially useful for the detection of nucleic acid molecules if suchmolecules are present in very low numbers.

An allele of profilaggrin may be identified by alterations inrestriction enzyme cleavage patterns. For example, sample and controlDNA is isolated, amplified (optionally) digested with one or morerestriction endonucleases, and fragment length sizes are determined, forexample by gel electrophoresis.

In yet another embodiment, any of a variety of sequencing reactionsknown in the art can be used to directly sequence the allele. Exemplarysequencing reactions include those based on techniques developed byMaxim and Gilbert (1997, Proc Natl Acad Sci USA 74, 560) or Sanger et al(1977, Proc Nat Acad Sci USA 74, 5463). It is also contemplated that anyof a variety of automated sequencing procedures may be utilized whenperforming the subject assays (see, for example Biotechniques (1995) 19,448), including sequencing by mass spectrometry (e.g. WO 94/16101; Cohenet al (1996) Adv Chromatogr 36, 127-162; and Griffin et al (1993) ApplBiochem Biotechnol 38, 147-159). It will be evident to one of skill inthe art that, for certain embodiments, the occurrence of only one, twoor three of the nucleic acid bases need be determined in the sequencingreaction. For instance, A-track or the like, e.g., where only onenucleic acid is detected, can be carried out.

A profilaggrin allele may be identified by using cleavage agents (suchas nuclease, hydroxylamine or osmium tetroxide and with piperidine) todetect mismatched bases in RNA/RNA or RNA/DNA or DNA/DNA heteroduplexes(Myers et al (1985) Science 230, 1242). In general, the art technique of“mismatch cleavage” starts by providing heteroduplexes formed byhybridizing (labeled) RNA or DNA containing the wild-type allele with asample. The double-stranded duplexes are treated with an agent whichcleaves single-stranded regions of the duplex such as which will existdue to base pair mismatches between the control and sample strands. Forinstance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybridstreated with 51 nuclease to enzymatically digest the mismatched regions.In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treatedwith hydroxylamine or osmium tetroxide and with piperidine in order todigest mismatched regions. After digestion of the mismatched regions,the resulting material is then separated by size, for example usingdenaturing polyacrylamide gel to determine the site of mutation. See,for example, Cotton et al (1988) Proc Natl Acad Sci USA 85, 4397; andSaleeba et al (1992) Methods Enzymol 217, 286-295. In a preferredembodiment, the control DNA or RNA can be labeled for detection.

In still another embodiment, the mismatch cleavage reaction employs oneor more proteins that recognize mismatched base pairs in double-strandedDNA (so called “DNA mismatch repair” enzymes). For example, the mutYenzyme of E. coli cleaves A at G/A mismatches and the thymidine DNAglycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al.(1994) Carcinogenesis 15, 1657-1662). According to an exemplaryembodiment, a probe based on a chosen profilaggrin allele is hybridizedto a cDNA or other DNA product from a test cell(s). The duplex istreated with a DNA mismatch repair enzyme, and the cleavage products, ifany, can be detected from electrophoresis protocols or the like. See,for example, U.S. Pat. No. 5,459,039.

Examples of other techniques for detecting alleles include, but are notlimited to, selective oligonucleotide hybridization, or selective primerextension. For example, oligonucleotide primers may be prepared in whichthe known mutation or nucleotide difference (e.g., in allelic variants)is placed centrally and then hybridized to target DNA under conditionswhich permit hybridization only if a perfect match is found (Saiki et al(1986) Nature 324, 163; Saiki et al (1989) Proc Natl Acad Sci USA 86,6230). Such allele specific oligonucleotide hybridization techniques maybe used to test one mutation or polymorphic region per reaction whenoligonucleotides are hybridized to PCR amplified target DNA or a numberof different mutations or polymorphic regions when the oligonucleotidesare attached to the hybridizing membrane and hyrbidized with labeledtarget DNA.

In another embodiment, identification of a profilaggrin allele may becarried out using an oligonucleotide ligation assay (OLA), as described,e.g., in U.S. Pat. No. 4,998,617 and in Landegren et al (1988, Science241, 1077-1080). The OLA protocol uses two oligonucleotides which aredesigned to be capable of hybridizing to abutting sequences of a singlestrand of a target. One of the oligonucleotides is linked to aseparation marker, e.g., biotinylated, and the other is detectablylabeled. If the precise complementary sequence is found in a targetmolecule, the oligonucleotides will hybridize such that their terminiabut, and create a ligation substrate. Ligation then permits the labeledoligonucleotide to be recovered using avidin, or another biotin ligand.Nickerson et al have described a nucleic acid detection assay thatcombines attributes of PCR and OLA (Nickerson et al (1990) Proc NatlAcad Sci USA 87, 8923-27). In this method, PCR is used to achieve theexponential amplification of target DNA, which is then detected usingOLA.

Several techniques based on this OLA method have been developed and canbe used to detect profilaggrin alleles. For example, U.S. Pat. No.5,593,826 discloses an OLA using an oligonucleotide having 3′-aminogroup and a 5′-phosphorylated oligonucleotide to form a conjugate havinga phosphoramidate linkage. In another variation of OLA described in Tobeet al (1997, Nucleic Acids Res 24, 3728), OLA combined with PCR permitstyping of two alleles in a single microtiter well. By marking each ofthe allele-specific primers with a unique hapten, i.e. digoxigenin andfluorescein, each OLA reaction can be detected by using hapten specificantibodies that are labeled with different enzyme reporters, alkalinephosphatase or horseradish peroxidase. This system permits the detectionof the two alleles using a high throughput format that leads to theproduction of two different colours.

Once the profilaggrin genotype of an individual has been determined,that individual can be categorised as having a high or lowpredisposition to a skin condition. Thus methods of the invention can beused to identify the profilaggrin genotype of an individual in order todetermine that individual's predisposition to a skin condition.Accordingly the invention provides a system for determining thepredisposition of an individual to a skin condition comprising means foridentifying the profilaggrin alleles present in the genome of a sampletaken from the individual.

The invention also provides for the use of a primer of the invention ina method of determining the predisposition of an individual to a skincondition as described above. Thus kits and assay components comprisingPCR primers and oligonucleotides for hybridisation as described aboveform further aspects of the invention.

The primer kit of the present invention is useful for identifyingprofilaggrin alleles using the polymerase chain reaction. The kitcomprises a set of pairs of single stranded DNA primers which can beannealed to sequences flanking the polymorphism and within orsurrounding the profilaggrin gene on the relevant chromosome in order toprime amplifying DNA synthesis of the gene itself. The complete set mayallow synthesis of all of the nucleotides of the profilaggrin allelecoding sequences, ie the exons, or may allow synthesis of less than theentire coding region. The set of primers preferably allows synthesis ofboth intron and exon sequences, as allelic variations may be found in aprofilaggrin gene intron. The kit can also contain DNA polymerase,preferably a thermophilic DNA polymerase, more preferably Taqpolymerase, yet more preferably Elongase (GIBCOBRL Life Technologies)and suitable reaction buffers. Such components are known in the art.

Having the ability to look at a patient on an individual basis willallow for a more accurate diagnosis and specific treatment plan.Genotyping is the process of obtaining an individual's DNA sequence byusing biological assays. By having a detailed account of an individual'sDNA sequence, their genome can then be compared to a reference genome,like that of the Human Genome Project, to assess the existing geneticvariations that can account for possible diseases. An individual'sgenetic make-up also plays a large role in how well they respond to acertain treatment, and therefore, knowing their genetic content canchange the type of treatment they receive. The system appliespharmacogenomics by using an individual's genome to provide a moreinformed and tailored cosmetic material prescription. Often, cosmeticmaterials are prescribed with the idea that it will work relatively thesame for everyone, but in the application of cosmetic materials, thereare a number of factors that must be considered. The detailed account ofgenetic information from the individual will help prevent adverseevents, allow for appropriate dosages, and create maximum efficacy withcosmetic material prescriptions. The pharmacogenomic process fordiscovery of genetic variants that predict adverse events to a specificcosmetic material has been termed toxgnostics.

In addition to specific treatment, personalized medicine can greatly aidthe advancements of preventive care. For instance, many women arealready being genotyped for certain mutations in the BRCA1 and BRCA2gene if they are predisposed because of a family history of breastcancer or ovarian cancer. As more causes of diseases are mapped outaccording to mutations that exist within a genome, the easier they canbe identified in an individual. Measures can then be taken to prevent adisease from developing. Even if mutations were found within a genome,having the details of their DNA can reduce the impact or delay the onsetof certain diseases. Having the genetic content of an individual willallow better guided decisions in determining the source of the diseaseand thus treating it or preventing its progression. This will beextremely useful for diseases like Alzheimer's or cancers that arethought to be linked to certain mutations in human DNA.

The system can be used to test efficacy and safety of a cosmeticmaterial specific to a targeted patient group/sub-group is companiondiagnostics. This technology is an assay that is developed during orafter a cosmetic material is made available on the market and is helpfulin enhancing the therapeutic treatment available based on theindividual. These companion diagnostics have incorporated thepharmacogenomic information related to the cosmetic material into theirprescription label in an effort to assist in making the most optimaltreatment decision possible for the patient.

Having an individual's genomic information can be significant in theprocess of developing cosmetic materials as they await approval from theFDA for public use. Having a detailed account of an individual's geneticmake-up can be a major asset in deciding if a patient can be chosen forinclusion or exclusion in the final stages of a clinical trial. Beingable to identify patients who will benefit most from a clinical trialwill increase the safety of patients from adverse outcomes caused by theproduct in testing, and will allow smaller and faster trials that leadto lower overall costs. In addition, cosmetic materials that are deemedineffective for the larger population can gain approval by the FDA byusing personal genomes to qualify the effectiveness and need for thatspecific cosmetic material or therapy even though it may only be neededby a small percentage of the population. Treatments can be morespecifically tailored to an individual and give insight into how theirbody will respond to the cosmetic material and if that cosmetic materialwill work based on their genome. The personal genotype can allowphysicians to have more detailed information that will guide them intheir decision in treatment prescriptions, which will be morecost-effective and accurate.

The system next generates gene-environmental factor interactions to helplifestyle recommendations. The system creates a matrix that correlatesgene and environmental impacts. One embodiment generates gene basedcosmetic material-cosmetic material interactions that allow thephysician or pharmacist to avoid health problems for the patient. FIG. 3shows a method 300 for predicting cosmetic material-cosmetic materialinteractions based on genetic data and clinical side effects, inaccordance with an embodiment of the present principles. The processincludes the following: At 310, construct a comprehensive gene-cosmeticmaterial-cosmetic material interactions (GDDIs) training dataset thatincludes all pharmaceutical, pharmacokinetic (PK), pharmacogenetic (PG),and pharmacodynamic (PD) GDDIs from multiple data sources for eachcosmetic material in a set of cosmetic materials under consideration. Inan embodiment, the multiple data sources can include, but are notlimited to, the following: gene sequencers, clinical trials; cosmeticmaterial development information; empirical information; a cosmeticmaterial bank; cosmetic material label information; an adverse eventreporting system (e.g., the FDA Adverse Event Reporting Systeminformation (FAERS)); and text mining from scientific documents (e.g.,search tool for interactions of chemicals (STITCH)). At step 320,construct side effect features for each of the cosmetic materials in theset from genetic panels for an individual and side effects associatedwith the cosmetic materials in the set. In an embodiment, the geneticpanels are generated by genetic sequencers, and all cosmetic materials'side effects, from which the side effect features are constructed, comefrom one or more of the following sources: clinical trials; cosmeticmaterial development; empirical information; FDA cosmetic material label(SIDER and DAILYMED®); FDA Adverse Event Reporting System (FAERS); andreal-world evidence. At 330, build, using the GDDIs training dataset, aGDDIs classifier for predicting whether or not a given cosmetic materialpair derived from the set of cosmetic materials results in adverseinteractions, and repeat this process for all possible cosmetic materialpairs derivable from the set of cosmetic materials. In an embodiment,the features used for building the classifier can include, but are notlimited to, the following: cosmetic material's clinical side effectkeywords; and other cosmetic material properties (e.g., chemicalstructures, protein targets, and so forth).

At 340, obtain predicted GDDIs from the classifier. At 350, for eachside effect, perform statistical test to determine whether that sideeffect is differentially shown between positive predicted GDDIs andnegative predicted GDDIs. In one embodiment, the term “positivepredicted GDDIs” refers to cosmetic materials pairs that cannot be takentogether given a patient genetic profile. In contrast, the term“negative predicted GDDIs” refers to cosmetic materials pairs that maybe safe to use together with a genetic profile.

Side effects are effects after taking a medicine, which are other thanthe intended therapeutic effects. Label side effects means the sideeffects are recorded in cosmetic material labels (for example, but notlimited to, SIDER database, DAILYMED®, and so forth). FDA side effectsmeans the side effects are recorded in, for example, but not limited to,the FDA Adverse Event Reporting System (FAERS). Consider, for example,the cosmetic material Ibuprofen as an example, DAILYMED® records its 249types of label side effects (e.g., abdominal discomfort, confusion, drymouth, vomiting, and weight loss), and FAERS records its 728 types ofFDA side effects (e.g., anxiety, ear ache, fatigue, tooth loss, sleepdisorder).

In 380, relative interactions between the different cosmetic materialsubstances can be determined by locating references in the interactiondata for each of the cosmetic material substances to others of thesubstances. Finally, in block 390, the relative interactions can berendered within a report such as a paper report or a graphical userinterface display. Optionally, an activatable link can be provided inthe display for selected ones of the cosmetic material substances forreordering the selected ones of the cosmetic material substances. Inthis way, the relative cosmetic material interactions resulting from thedispensing of multiple different cosmetic material substances based onpatient genetic data can be determined without requiring a tediousmanual process of looking up cosmetic material interaction data for eachsubstance and manually correlating the cosmetic material interactiondata for the specific combination of dispensed substances.

The system can also perform GDDI discovery and prediction that usesmolecular structure similarity information derived fromfingerprint-based modeling. Identifying new GDDIs using structuralsimilarity is based on the basic idea that if cosmetic material Ainteracts with cosmetic material B, and cosmetic material C isstructurally similar to A, then C should also interact with B (theargument also follows if A is replaced with B). Hence, by combiningknowledge of known interactions with structural similarity it ispossible to identify new interactions. The process uses a list ofcosmetic material-cosmetic material interactions from CosmeticmaterialBank (step 1), structural similarity computation was carried outusing molecular fingerprints (step 2), apply gene-cosmetic materialinteraction to similar cosmetic materials, and a new list ofgene-cosmetic material interactions can be inferred.

Structural similarity can be identified in three steps: 1) Collectingand processing cosmetic material structures: Information on thestructures of the compounds in Cosmetic materialBank is retrieved alongwith the SMILE code (a chemical notation representing a chemicalstructure in linear textual form). 2) Structural representation:BIT_MACCS (MACCS Structural Keys Bit packed) fingerprints are calculatedfor all molecules included in the study and each molecule is representedas a bit vector that codes the presence or absence of structuralfeatures where each feature is assigned a specific bit position. 3)Similarity measures, computation, and data representation: Differentmeasures are used to compare similarity between two molecularfingerprints. In one embodiment, the molecular fingerprints werecompared using Tanimoto coefficient (TC). The TC can span values between0 and 1, where 0 means ‘maximum dissimilarity’ and 1 means ‘maximumsimilarity.’ The TC between two fingerprint representations A and B isdefined as the number of features present in the intersection of bothfingerprints A and B divided by the number of features present in theunion of both fingerprints. Next, for each cosmetic material affected bya particular gene, the process predicts new gene based DDIs. Oneembodiment predicts new DDIs reduces to matrix multiplication of thematrices M1, which consists of the established interactions, and M2,which consists of the similarity matrix.

The pharmacogenomic information can be applied to cosmetic materiallabeling. One embodiment may contain information on genomic biomarkersand can describe:

-   -   Cosmetic material exposure and clinical response variability    -   Risk for adverse events    -   Genotype-specific dosing    -   Mechanisms of cosmetic material action    -   Polymorphic cosmetic material target and disposition genes

The information may include specific actions to be taken based on thebiomarker information. Pharmacogenomic information can appear indifferent sections of the labeling depending on the actions. Biomarkersin the table include but are not limited to germ-line or somatic genevariants, functional deficiencies, expression changes, and chromosomalabnormalities; selected protein biomarkers that are used to selectpatients for treatment are also included.

In one embodiment, the process includes constructing a gene-cosmeticmaterial interactions training dataset that includes pharmaceutical,pharmacokinetic or pharmacodynamics, and pharmacogenomics cosmeticmaterial-cosmetic material interactions for each cosmetic material;constructing side effect features for each of the plurality of cosmeticmaterials from side effects associated with the plurality of cosmeticmaterials; running a gene-cosmetic material-cosmetic materialinteractions classifier that predicts adverse cosmetic material-cosmeticmaterial interactions for cosmetic material pairs and the genetic scan;and for each of the side effects, performing a Fisher's exact test todetermine predicted gene-cosmetic material-cosmetic materialinteractions. Fisher's exact testis a statistical significance test usedin the analysis of contingency tables. It is one of a class of exacttests, so called because the significance of the deviation from a nullhypothesis (e.g., P-value) can be calculated exactly, rather thanrelying on an approximation that becomes exact in the limit as thesample size grows to infinity, as with many statistical tests.

FIG. 4 shows a deep learning machine using deep convolutionary neuralnetworks for detecting genetic based cosmetic material-cosmetic materialinteraction. One embodiment uses an AlexNet: 8-layer architecture, whileanother embodiment uses a VGGNet: 16-layer architecture (each poolinglayer and last 2 FC layers are applied as feature vector). For cosmeticmaterials, the indications of use and other cosmetic materials usedcapture most of many important covariates. One embodiment access datafrom SIDER (a text-mined database of cosmetic material package inserts),the Offsides database that contains information complementary to thatfound in SIDER and improves the prediction of protein targets andcosmetic material indications, and the Twosides database of minedputative DDIs also lists predicted adverse events, all available at thehttp://PharmGKB.org Web site.

The system of FIG. 4 receives data on adverse events strongly associatedwith indications for which the indication and the adverse event have aknown causative relationship. A cosmetic material-event association issynthetic if it has a tight reporting correlation with the indication(ρ≥0.1) and a high relative reporting (RR) association score (RR≥2).Cosmetic materials reported frequently with these indications were 80.0(95% CI, 14.2 to 3132.8; P<0.0001, Fisher's exact test) times as likelyto have synthetic associations with indication events. Diseaseindications are a significant source of synthetic associations. The moredisproportionately a cosmetic material is reported with an indication (xaxis), the more likely that cosmetic material will be syntheticallyassociated. For example, adverse events strongly associated withcosmetic materials are retrieved from the cosmetic material's packageinsert. These cosmetic material-event pairs represent a set of knownstrong positive associations.

Adverse events related to sex and race are also analyzed. For example,for physiological reasons, certain events predominantly occur in males(for example, penile swelling and azoospermia). Cosmetic materials thatare disproportionately reported as causing adverse events in males weremore likely to be synthetically associated with these events. Similarly,adverse events that predominantly occur in either relatively young orrelatively old patients are analyzed.

“Off-label” adverse event data is also analyzed, and off-label usesrefer to any cosmetic material effect not already listed on the cosmeticmaterial's package insert. For example, the SIDER database, extractedfrom cosmetic material package inserts, lists 48,577 cosmeticmaterial-event associations for 620 cosmetic materials and 1092 adverseevents that are also covered by the data mining. Offsides recovers 38.8%(18,842 cosmetic material-event associations) of SIDER associations fromthe adverse event reports. Thus, Offsides finds different associationsfrom those reported during clinical trials before cosmetic materialapproval.

Polypharmacy side effects for pairs of cosmetic materials (Twosides) arealso analyzed. These associations are limited to only those that cannotbe clearly attributed to either cosmetic material alone (that is, thoseassociations covered in Offsides). The database contains an significantassociations for which the cosmetic material pair has a higherside-effect association score, determined using the proportionalreporting ratio (PRR), than those of the individual cosmetic materialsalone. The system determines pairwise similarity metrics between allcosmetic materials in the Offsides and SIDER databases. The system canpredict shared protein targets using cosmetic material-effectsimilarities. The side-effect similarity score between two cosmeticmaterials is linearly related to the number of targets that thosecosmetic materials share.

The system can determine relationships between the proportion of sharedindications between a pair of cosmetic materials and the similarity oftheir side-effect profiles in Offsides. The system can use side-effectprofiles to suggest new uses for old cosmetic materials. While thepreferred system predicts existing therapeutic indications of knowncosmetic materials, the system can recommend cosmetic materialrepurposing using cosmetic material-effect similarities in Offsides.

Corroboration of class-wide interaction effects with EMRs. The systemcan identify DDIs shared by an entire cosmetic material class. Theclass-class interaction analysis generates putative cosmetic materialclass interactions. The system analyzes laboratory reports commonlyrecorded in EMRs that may be used as markers of these class-specificDDIs.

The system can be used systematic cosmetic material surveillance. TheFDA manages a collection of adverse cosmetic material event reports tomonitor the safety of cosmetic materials. They rely on physicians,pharmaceutical companies, and patients to volunteer these reports. Sincereporting is not mandatory, many adverse cosmetic material events thatoccur are never reported to the FDA. To address this issue, anembodiment of the present invention uses an algorithm to inferunreported adverse cosmetic material events. This embodiment relies onthe fact that many adverse events occur together. For example, nauseaand vomiting commonly manifest together. Therefore, if a cosmeticmaterial is observed to causes nausea, it can be inferred that it alsocauses vomiting.

The successful prediction of side effects before a cosmetic materialenters clinical trials can be done. Chemical informatics techniques canpredict cosmetic material side effects by comparing the structuralsimilarity of cosmetic materials. Protein structural similarity islearned by the deep learning system to predict cosmetic material sideeffects. More recently, network and chemical properties are used forpredictive models of cosmetic material effects and leverage the system'scomprehensive database of known cosmetic material effects.

In another aspect, a method for analyzing a disease state of a subjectincludes capturing a first liquid biopsy from the subject; providing theliquid biopsy to a genetic analyzer to identify the subject's geneticinformation of a first disease state at a first time point; searchingfor genetically similar patients and predicting a mutation of thedisease into a second disease state at a second time point; analyzing atreatment database and recommending a treatment given the first andsecond disease states; capturing a second liquid biopsy from the subjectat a second time point; providing the second liquid biopsy to thegenetic analyzer to identify the subject's genetic information; and ifthe genetic information from the second time point matches the predictedmutation, continuing the recommended treatment for the subject andotherwise changing the recommended treatment.

In yet another aspect, a method to detect abnormal cellular activitiesincludes sequencing of cell-free nucleic acid with a genetic analyzer ora DNA sequencer; comparing current sequence reads with prior sequencereads from at least two time points; detecting a mutation of thecell-free nucleic acid and updating a diagnostic confidence indicationaccordingly; and detecting the presence or absence of genetic alterationand/or amount of genetic variation in an individual based on thediagnostic confidence indication of the sequence read.

In a further aspect, a method for analyzing a disease state of a subjectincludes capturing a first liquid biopsy from the subject; providing theliquid biopsy to a genetic analyzer to identify the subject's geneticinformation of a first disease state at a first time point; searchingfor genetically similar subject profiles and predicting a mutation ofthe disease into a second disease state at a second time point;capturing a second liquid biopsy from the subject; providing the secondliquid biopsy to a genetic analyzer to identify the subject's geneticinformation at a second time point; and if the genetic information fromthe second time point matches the predicted mutation, continuing therecommended treatment for the subject and otherwise changing therecommended treatment.

In another aspect disclosed herein is a method for analyzing a diseasestate of a subject by characterizing the subject's genetic informationat two or more time points with a genetic analyzer, e.g., a DNAsequencer; and using the information from the two or more time points toproduce an adjusted test result in the characterization of the subject'sgenetic information.

In another aspect, a method detects a trend in the amount of mutationcancer polynucleotides in a sample from a subject over time bydetermining a frequency of the cancer polynucleotides at a plurality oftime points; determining an error range for the frequency at each of theplurality of time points; determining, between an earlier and later timepoint, whether error ranges (1) overlap, indicating stability offrequency, (2) an increase at the later time point outside the errorrange, indicating increase in frequency or (3) a decrease at the latertime point outside the error range, indicating decrease in frequency.

In yet another aspect, a method detects mutation cellular activities bysequencing of cell-free nucleic acid with a genetic analyzer, e.g., aDNA sequencer; comparing later (e.g., current) sequence reads with priorsequence reads from at least two time points and updating a diagnosticconfidence indication accordingly; and detecting the presence or absenceof genetic alteration and/or amount of genetic variation in anindividual based on the diagnostic confidence indication of the sequenceread. A genetic analyzer includes any system for genetic analysis, e.g.,by sequencing (DNA sequencer) or hybridization (microarray, fluorescentin situ hybridization, bionanogenomics) or other.

In another aspect, a method detects a mutation in a cell-free orsubstantially cell free sample obtained from a subject by generatingconsensus sequences by comparing later (e.g., current) sequence reads bya genetic analyzer, e.g., a DNA sequencer, with prior sequence readsfrom a prior period and updating a diagnostic confidence indicationbased on the prior sequence reads, each consensus sequence correspondingto a unique polynucleotide among a set of tagged parent polynucleotides,and generating a genetic profile of extracellular polynucleotides in thesubject, wherein the genetic profile comprises a plurality of dataresulting from copy number variation or mutation analyses.

In another aspect disclosed herein is a method to detect mutationcellular activities by providing at least one set of tagged parentpolynucleotides, and for each set of tagged parent polynucleotides;amplifying the tagged parent polynucleotides in the set to produce acorresponding set of amplified progeny polynucleotides; with a geneticanalyzer, e.g., a DNA sequencer, sequencing a subset of the set ofamplified progeny polynucleotides, to produce a set of sequencing reads;and collapsing the set of sequencing reads to generate a set ofconsensus sequences by comparing current sequence reads with priorsequence reads from at least one prior period and updating diagnosticconfidence indication accordingly, each consensus sequence correspondingto a unique polynucleotide among the set of tagged parentpolynucleotides.

In yet another aspect, a method detects a mutation in a cell-free orsubstantially cell free sample obtained from a subject by sequencingextracellular polynucleotides from a bodily sample from a subject with agenetic analyzer, e.g., a DNA sequencer; for each of the extracellularpolynucleotide, generating a plurality of sequencing reads; filteringout reads that fail to meet a set threshold; mapping sequence readsderived from the sequencing onto a reference sequence; identifying asubset of mapped sequence reads that align with a variant of thereference sequence at each mappable base position; for each mappablebase position, calculating a ratio of (a) a number of mapped sequencereads that include a variant as compared to the reference sequence, to(b) a number of total sequence reads for each mappable base position;and comparing current sequence reads with prior sequence reads from atleast on other time point and updating a diagnostic confidenceindication accordingly.

The method identifies one or more evolutionary paths of escape andevolved tumor treatment(s). These paths are caused by various drivers.For example, as shown in FIG. 5A, common aberrations in cancer genomescan lead to the abnormal chromosome numbers (aneuploidy) and chromosomestructures of a cancer genome. In FIG. 5A, lines indicate the genomewith germline genome on top and cancer genome with somatic aberrationsbelow. Double lines are used when differentiating heterozygous andhomozygous changes is useful. Dots represent single nucleotide changes,whereas lines and arrows represent structural changes.

FIG. 5B shows an exemplary system to detect the evolutionary paths ofescape for skin cancer. The system can be a Hidden Markov model (HMM),which is a statistical Markov model in which the system being modeled isassumed to be a Markov process with unobserved (hidden) states. As knownto those skilled in the art, an HMM can be presented as the simplestdynamic Bayesian network. In simpler Markov models (like a Markovchain), the state is directly visible to the observer, and therefore thestate transition probabilities are the only parameters. In a hiddenMarkov model, the state is not directly visible, but output, dependenton the state, is visible. Each state has a probability distribution overthe possible output tokens. Therefore the sequence of tokens generatedby an HMM gives some information about the sequence of states. A hiddenMarkov model can be considered a generalization of a mixture model wherethe hidden variables (or latent variables), which control the mixturecomponent to be selected for each observation, are related through aMarkov process rather than independent of each other. As shown in FIG.5B, the HMM is typically defined by a set of hidden states, a matrix ofstate transition probabilities and a matrix of emission probabilities.Each hidden state has different statistical properties.

Mutations and genetic alterations including in copy number, for example,allelic imbalances, chromosomal copy number changes, such asamplifications, deletions, aneuploidy, loss of heterozygosity, andmicro-satellite instability are often found to be associated with adisease state, for example, cancer. It has been observed thatalterations in chromosomal copy number and loss of heterozygosity (LOH)are forms of genetic changes that often signal the activation ofoncogenes and inactivation of tumor suppressor genes (anti-oncogenes).Variations in the form of copy number polymorphisms (CNP) can also occurin normal individuals. Identification of the loci implicated in theseaberrations can generate anchor points which facilitate oncogenomics andtoxicogenomics studies. Subsequently the shared LOH and aberrant CNregions can be used to partition the transcriptome data and track thedifferential transcript expression in the affected genomic segments.Locating and exploring such alteration events is an important researchapproach toward understanding the cause and progression of disease. Fordiploid organisms, the abnormal chromosomal state results when thenormal diploid distribution is perturbed, resulting in changes that caninclude, for example, deletions, amplifications and translocations.Deletions can be of a partial chromosome ranging from micro-deletions onthe order of several kb to macro-deletions of mega bases, entire arms ofa chromosome or entire chromosomes. Amplifications can range frompartial chromosomal amplifications to gains of a single copy of achromosome to multiple copy gains of one or more chromosomes.Translocations generally comprise parts of a first chromosome beingtranslocated to another chromosome.

FIG. 5B shows the general architecture of an instantiated HMM formutation detection. Each oval shape X1, X2, X3 represents a randomvariable that can adopt any of a number of values. The random variablex(t) is the hidden state at time t (x(t) ∈{x1, x2, x3}). The randomvariable y(t) is the observation at time t (with y(t) ∈{y1, y2, y3,y4}). The arrows in the diagram (often called a trellis diagram) denoteconditional dependencies. The conditional probability distribution ofthe hidden variable x(t) at time t, given the values of the hiddenvariable x at all times, depends only on the value of the hiddenvariablex(t-1): the values at time t-2 and before have no influence.This is called the Markov property. Similarly, the value of the observedvariable y(t) representing the mutation conditions only depends on thevalue of the hidden variable x(t) (both at timet).

In FIG. 5B, the state space of the hidden variables is discrete, whilethe observations themselves can either be discrete (typically generatedfrom a categorical distribution) or continuous (typically from aGaussian distribution). The parameters of a hidden Markov model are oftwo types, transition probabilities and emission probabilities (alsoknown as output probabilities). The transition probabilities control theway the hidden state at time is chosen given the hidden state at time.The hidden state space is assumed to consist of one of possible values,modeled as a categorical distribution. (See the section below onextensions for other possibilities.) This means that for each of thepossible states that a hidden variable at time can be in, there is atransition probability from this state to each of the possible states ofthe hidden variable at time, for a total of transition probabilities.Note that the set of transition probabilities for transitions from anygiven state must sum to 1. Thus, the matrix of transition probabilitiesis a Markov matrix. Because any one transition probability can bedetermined once the others are known, there are a total of transitionparameters.

In addition, for each of the possible states, there is a set of emissionprobabilities governing the distribution of the observed variable at aparticular time given the state of the hidden variable at that time. Thesize of this set depends on the nature of the observed variable. Forexample, if the observed variable is discrete with possible values,governed by a categorical distribution, there will be separateparameters, for a total of emission parameters over all hidden states.On the other hand, if the observed variable is an dimensional vectordistributed according to an arbitrary multivariate Gaussiandistribution, there will be parameters controlling the means andparameters controlling the covariance matrix, for a total of emissionparameters. (In such a case, unless the value of is small, it may bemore practical to restrict the nature of the covariances betweenindividual elements of the observation vector, e.g. by assuming that theelements are independent of each other, or less restrictively, areindependent of all but a fixed number of adjacent elements).

The HMM method can model a somatic evolution of cancer. The methodincludes modeling genetic instability, which results in abnormal numbersof chromosomes or aneuploidy, elevated mutation rates, and altereddistributions of mutational patterns.

The method can identify one or more cancer mutation drivers. Thesedrivers include those that disrupt cellular signaling pathways essentialfor multicellular organisms and possible mutations that increase somaticfitness of cancer cells. The method can include identifying dynamics oftumor progression in a population based on interactions with anenvironment. The method includes collecting repeated geneticobservations to enhance statistical inference about the evolution oftumors.

The method includes recommending or providing a therapeutic regimen inanticipation of the one or more escape paths. Diagnosis of cancer can bedone by analyzing the genetic variants, even in the presence of noise.The analysis can be based on the frequency of Sequence Variants or Levelof CNV and a diagnosis confidence indication or level for detectinggenetic variants in the noise range can be established. The processincreases the diagnosis confidence using a plurality of measurements toincrease confidence of Diagnosis (6), or alternatively usingmeasurements at a plurality of time points to determine whether canceris advancing, in remission or stabilized. The diagnostic confidence canbe used to identify disease states. For example, cell freepolynucleotides taken from a subject can include polynucleotides derivedfrom normal cells, as well as polynucleotides derived from diseasedcells, such as cancer cells. Polynucleotides from cancer cells may beargenetic variants, such as somatic cell mutations and copy numbervariants. When cell free polynucleotides from a sample from a subjectare sequenced, these cancer polynucleotides are detected as sequencevariants or as copy number variants. The relative amount of tumorpolynucleotides in a sample of cell free polynucleotides is referred toas the “tumor burden.” Measurements of a parameter, whether or not theyare in the noise range, may be provided with a confidence interval.Tested over time, one can determine whether a cancer is advancing,stabilized or in remission by comparing confidence intervals over time.Where the confidence intervals do not overlap, this indicates thedirection of disease.

In one implementation, using measurements from a plurality of samplescollected substantially at once or over a plurality of time points, thediagnostic confidence indication for each variant can be adjusted toindicate a confidence of predicting the observation of the CNV ormutation. The confidence can be increased by using measurements at aplurality of time points to determine whether cancer is advancing, inremission or stabilized. The diagnostic confidence indication can beassigned by any of a number of known statistical methods is assigned andcan be based, at least in part, on the frequency at which themeasurements are observed over a period of time. For example, astatistical correlation of current and prior results can be done.Alternatively, for each diagnosis, a hidden Markov model can be built,such that a maximum likelihood or maximum a posteriori decision can bemade based on the frequency of occurrence of a particular test eventfrom a plurality of measurements or a time points. As part of thismodel, the probability of error and resultant diagnostic confidenceindication for a particular decision can be output as well. In thismanner, the measurements of a parameter, whether or not they are in thenoise range, may be provided with a confidence interval. Tested overtime, one can increase the predictive confidence of whether a cancer isadvancing, stabilized or in remission by comparing confidence intervalsover time. Two time points can be separated by about a month to about ayear, about a year to about 5 years, or no more than about three months.

The HMM detect with high sensitivity genetic variation in a sample ofinitial genetic material. The methods involve using one to three of thefollowing tools: First, the efficient conversion of individualpolynucleotides in a sample of initial genetic material intosequence-ready tagged parent polynucleotides, so as to increase theprobability that individual polynucleotides in a sample of initialgenetic material will be represented in a sequence-ready sample. Thiscan produce sequence information about more polynucleotides in theinitial sample. Second, high yield generation of consensus sequences fortagged parent polynucleotides by high rate sampling of progenypolynucleotides amplified from the tagged parent polynucleotides, andcollapsing of generated sequence reads into consensus sequencesrepresenting sequences of parent tagged polynucleotides. This can reducenoise introduced by amplification bias and/or sequencing errors, and canincrease sensitivity of detection. Third, the noise in the detection ofmutations and copy number variations is reduced by comparing priorsample analysis with the current sample and increasing a diagnosticconfidence indication if the same mutations and copy number variationshave appeared in prior analysis and otherwise decreasing the diagnosticconfidence indication if this is the first time the sequence isobserved.

FIG. 5C shows an exemplary model generated by the system of FIG. 2B forinferring tumor phylogeny from next-generation sequencing data. Thesubclones are related to each other by an evolutionary process ofacquisition of mutations. In this example, the three clones (leaf nodes)are characterized by different combinations of the four singlenucleotide variant (SNV) sets A, B, C, and D. The percentages on theedges of the tree indicate the fraction of cells with this particularset of SNVs, e.g., 70% of all cells carry A, 40% additionally carry B,and only 7% carry A, B, and D.

FIG. 5D shows an exemplary a heterogeneous collection of normal cellsand cancer subclones developed during an evolutionary history of atumor. The evolutionary history of a tumor gives rise to a heterogeneouscollection of normal cells (small discs) and cancer subclones (largediscs, triangles, squares). Internal nodes that have been fully replacedby their descendants (like the one carrying SNV sets A and B without Cor D) are no longer part of the tumor.

Embodiments of the invention can take the form of an entirely hardwareembodiment, an entirely software embodiment or an embodiment containingboth hardware and software elements. In a preferred embodiment, theinvention is implemented in software, which includes but is not limitedto firmware, resident software, microcode, and the like. Furthermore,the invention can take the form of a computer program product accessiblefrom a computer-usable or computer-readable medium providing programcode for use by or in connection with a computer or any instructionexecution system.

For the purposes of this description, a computer-usable or computerreadable medium can be any apparatus that can contain, store,communicate, or transport the program for use by or in connection withthe instruction execution system, apparatus, or device. The medium canbe an electronic, magnetic, optical, electromagnetic, infrared, orsemiconductor system (or apparatus or device). Examples of acomputer-readable medium include a semiconductor or solid state memory,magnetic tape, a removable computer diskette, a random access memory(RAM), a read-only memory (ROM), a rigid magnetic disk and an opticaldisk. Current examples of optical disks include compact disk-read onlymemory (CD-ROM), compact disk-read/write (CD-R/W) and DVD.

A data processing system suitable for storing and/or executing programcode will include at least one processor coupled directly or indirectlyto memory elements through a system bus. The memory elements can includelocal memory employed during actual execution of the program code, bulkstorage, and cache memories which provide temporary storage of at leastsome program code in order to reduce the number of times code must beretrieved from bulk storage during execution. Input/output or I/Odevices (including but not limited to keyboards, displays, pointingdevices, etc.) can be coupled to the system either directly or throughintervening I/O controllers. Network adapters may also be coupled to thesystem to enable the data processing system to become coupled to otherdata processing systems or remote printers or storage devices throughintervening private or public networks. Modems, cable modem and Ethernetcards are just a few of the currently available types of networkadapters.

The pattern recognizer can identify beauty trends derived from Google'ssearch data. Trends is a numeric/historic representation of the relativevolume of searches made on Google. It creates indexes that show trendinginstead of actual volume (a big difference between Trends and KeywordPlanner); this data can be mined for actionable insights you just can'tget from Keyword Planner. The results are broken out into two separategraphs: historic trending (interest over time) and localized (regional)behavior. Trending Stories rely on technology from the Knowledge Graphacross Google Search, Google News, and YouTube to detect when topics aretrending on these three platforms. The Knowledge Graph enables thesystem to connect beauty trends with real-world things and places. Thealgorithm for trending stories groups topics together that are trendingat the same time on Google News, Google Search, and YouTube and ranksstories based on the relative spike in volume and the absolute volume ofsearches.

In one embodiment, the pattern recognizer may obtain a patterndefinition in a simple format; predict several time steps in future byusing Markov models; optimize results based on its predictions; detecttransition between patterns; abstract data and extract information toinfer higher levels of knowledge; combine higher and lower levels ofinformation to understand about the patient and clinical behaviors;infer from multi-temporal (different time scales) data and associatedinformation; using variable order Markov models, and/or reduce noiseover time by employing clustering algorithms, such as k-meansclustering.

For example, K vectors are randomly chosen and assigned as a clustercenter for applying k-means clustering algorithms. In patternrecognition, the k-means is a method for classifying objects based onthe closest training examples in the feature space. k-NN is a type ofinstance based learning, or lazy learning, where the function is onlyapproximated locally and all computation is differed untilclassification. The Euclidian distance between different patterns inthis vector space may be used to find clusters of patterns. The systemmay assign a new input vector to its closest cluster center and may movethat cluster towards the input vector by a fraction of the Euclideandistance between them.

The system may use knowledge-based components such as a knowledge-basedrepository (KB). The repository may include clinical information. Forexample, it may include that “eating salt-rich food causes bloodpressure to increase.” The information may be stored in a variety offormats based on the type of inference employing them. Theknowledge-based repository may act as a repository for some or all ofthe referenced knowledge. For example, it can include reference valuesfor certain consents and variables used for inference. Accordingly, oneor more layers (e.g. a hierarchical pattern processing layer or PatternEngine) may subscribe to information from the knowledge-basedrepository. For example, one or more of the services may query theknowledge-based repository when making an inference.

In one embodiment, the knowledge-based repository may aggregate relevantclinical and/or behavioral knowledge from one or more sources. In anembodiment, one or more clinical and/or behavioral experts may manuallyspecify the required knowledge. In another embodiment, an ontology-basedapproach may be used. For example, the knowledge-based repository mayleverage the semantic web using techniques, such as statisticalrelational learning (SRL). SRL may expand probabilistic reasoning tocomplex relational domains, such as the semantic web. The SRL mayachieve this using a combination of representational formalisms (e.g.,logic and/or frame based systems with probabilistic models). Forexample, the SRL may employ Bayesian logic or Markov logic. For example,if there are two objects—‘Asian male’ and ‘smartness’, they may beconnected using the relationship ‘asian males are smart’. Thisrelationship may be given a weight (e.g., 0.3). This relationship mayvary from time to time (populations trend over years/decades). Byleveraging the knowledge in the semantic web (e.g., all references anddiscussions on the web where ‘asian male’ and ‘smartness’ are used andassociated) the degree of relationship may be interpreted from thesentiment of such references (e.g., positive sentiment: TRUE; negativesentiment: FALSE). Such sentiments and the volume of discussions maythen be transformed into weights. Accordingly, although the systemoriginally assigned a weight of 0.3, based on information from semanticweb about Asian males and smartness, may be revised to 0.9.

In an embodiment, Markov logic may be applied to the semantic web usingtwo objects: first-order formulae and their weights. The formulae may beacquired based on the semantics of the semantic web languages. In oneembodiment, the SRL may acquire the weights based on probability valuesspecified in ontologies. In another embodiment, where the ontologiescontain individuals, the individuals can be used to learn weights bygenerative learning. In some embodiments, the SRL may learn the weightsby matching and analyzing a predefined corpora of relevant objectsand/or textual resources. These techniques may be used to not only toobtain first-order waited formulae for clinical parameters, but alsogeneral information. This information may then be used when makinginferences.

For example, if the first order logic is ‘obesity causes hypertension,there are two objects involved: obesity and hypertension. If data onpatients with obesity and as to whether they were diagnosed withdiabetes or not is available, then the weights for this relationship maybe learnt from the data. This may be extended to non-clinical examplessuch as person's mood, beliefs etc.

The pattern recognizer may use the temporal dimension of data to learnrepresentations. The pattern recognizer may include a pattern storagesystem that exploits hierarchy and analytical abilities using ahierarchical network of nodes. The nodes may operate on the inputpatterns one at a time. For every input pattern, the node may provideone of three operations: 1. Storing patterns, 2. Learning transitionprobabilities, and 3. Context specific grouping.

A node may have a memory that stores patterns within the field of view.This memory may permanently store patterns and give each pattern adistinct label (e.g. a pattern number). Patterns that occur in the inputfield of view of the node may be compared with patterns that are alreadystored in the memory. If an identical pattern is not in the memory, thenthe input pattern may be added to the memory and given a distinctpattern number. The pattern number may be arbitrarily assigned and maynot reflect any properties of the pattern. In one embodiment, thepattern number may be encoded with one or more properties of thepattern.

In one embodiment, patterns may be stored in a node as rows of a matrix.In such an embodiment, C may represent a pattern memory matrix. In thepattern memory matrix, each row of C may be a different pattern. Thesedifferent patterns may be referred to as C-1, C-2, etc., depending onthe row in which the pattern is stored.

The nodes may construct and maintain a Markov graph. The Markov graphmay include vertices that correspond to the store patterns. Each vertexmay include a label of the pattern that it represents. As new patternsare added to the memory contents, the system may add new vertices to theMarkov graph. The system may also create a link between to vertices torepresent the number of transition events between the patternscorresponding to the vertices. For example, when an input pattern isfollowed by another input pattern j for the first time, a link may beintroduced between the vertices i and j and the number of transitionevents on that link may be set to 1. System may then increment thenumber of transition counts on the link from i and j whenever a patternfrom i to pattern j is observed. The system may normalize the Markovgraph such that the links estimate the probability of a transaction.Normalization may be achieved by dividing the number of transitionevents on the outgoing links of each vertex by the total number oftransition events from the vertex. This may be done for all vertices toobtain a normalized Markov graph. When normalization is completed, thesum of the transition probabilities for each node should add to 1. Thesystem may update the Markov graph continuously to reflect newprobability estimates.

The system may also perform context-specific grouping. To achieve this,the system may partition a set of vertices of the Markov graph into aset of temporal groups. Each temporal group may be a subset of that setof vertices of the Markov graph. The partitioning may be performed suchthat the vertices of the same temporal group are highly likely to followone another.

The node may use Hierarchical Clustering (HC) to for the temporalgroups. The HC algorithm may take a set of pattern labels and theirpair-wise similarity measurements as inputs to produce clusters ofpattern labels. The system may cluster the pattern labels such thatpatterns in the same cluster are similar to each other.

In one embodiment, the probability of a transition between two patternsmay be used as the similarity between those patterns for the HCalgorithm. The similarity metric may be used to cluster medical patternsthat are likely to follow one another into the same cluster. The HCalgorithm may be configured such that patterns that are unlikely tofollow each other fall into different clusters. A cluster of a set ofpatterns that are likely to follow each other in time may be referred toas a temporal group. The HC algorithm may start with all store patternsand separate clusters and then recursively merge clusters with thegreatest similarity. This may be used to obtain a treelike structure(e.g. a dendrogram) with a single cluster (which may contain allpatterns) at the top of the tree and the individual patterns at thebottom (e.g. each pattern in its own cluster). The system may achievethe desired clustering for temporal grouping (e.g. somewhere between thebottom and a top of the dendrogram) by defining a suitable criteria. Forexample, one criterion could be to cut the tree at a level where thesize of the largest cluster does not exceed a particular value. The nodemay have a design perimeter that sets the maximum number of clusters ortemporal groups of the node. The desired temporal groups may be achievedby selecting a level of the dendrogram that gives the number of temporalgroups closest to and less than the configured maximum number oftemporal groups. These temporal groups may be updated as the Markovtransition probabilities are updated. These steps may be performedperiodically during the learning process. The learning process may bestopped once the temporal groups have sufficiently stabilized.

Once a node has completed its learning process, it may be used forsensing and/or inference. The characteristics of the input to the nodein sensing may be identical to those used during learning. For example,objects may move under the field of view of the node and the node maysee portions of those objects. The resulting patterns may be used asinputs to the node.

A node used for sensing and/or inference may produce an output for everyinput pattern. A node may also use a sequence of patents to produce anoutput. In one embodiment, it can be assumed that the outputs areproduced based on instantaneous inputs. Under this assumption, theMarkov graph may not be used during the sensing phase. For example, itmay be discarded once the temporal groups within the node are completed.

For every input pattern, the node may produce an output factor thatindicates the degree of membership of the input pattern and each of itstemporal groups. However, the current input pattern may not perfectlymatch any of the patterns stored in memory. Accordingly, in oneembodiment, the closeness of the input pattern to every pattern storedin memory will be determined. For example, let di be the distance of theith stored pattern from the input pattern. The larger this distance is,the smaller the match between the input pattern and the stored patternbecomes. Assuming that the probability that an input pattern matches astored pattern falls off as a Gaussian function of the Euclideandistance, the probability that the input pattern matches the ith storedpattern can be calculated as being proportional to e-d2i/α, where α is aparameter of the node. Calculating this for every stored pattern maygive the closeness of the current input pattern to all the vertices ofthe Markov graph.

Degree of membership of the input pattern in each temporal group may bedetermined by the maximum of its closeness to each of the verticeswithin the temporal group. This results in a length equal to the numberof temporal groups, with each component of the factor indicating thedegree of membership of the input pattern in the corresponding temporalgroup. This factor may then be used normalize the sum to unity. Thesenormalized memberships may be used as estimates of probability ofmembership in each temporal group. This normalized degree of membershipmay also be used as an output of the node. The output may be a histogramgiving estimates of probability of membership of the current inputpattern and each of the temporal groups of the node.

As data is fed into the pattern recognizer, the transition probabilitiesfor each pattern and pattern-of-patterns may be updated based on theMarkov graph. This may be achieved by updating the constructedtransition probability matrix. This may be done for each pattern inevery category of patterns. Those with higher probabilities may bechosen and placed in a separate column in the database called aprediction list.

Logical relationships among the patterns may be manually defined basedon the clinical relevance. This relationship is specified as first-orderlogic predicates along with probabilities. These probabilities may becalled beliefs. In one embodiment, a Bayesian Belief Network (BBN) maybe used to make predictions using these beliefs. The BBN may be used toobtain the probability of each occurrence. These logical relationshipsmay also be based on predicates stored the knowledge base.

The pattern recognizer may also perform optimization for thepredictions. In one embodiment, this may be accomplished by comparingthe predicted probability for a relationship with its actual occurrence.Then, the difference between the two may be calculated. This may be donefor p occurrences of the logic and fed into a K-means clusteringalgorithm to plot the Euclidean distance between the points. A centroidmay be obtained by the algorithm, forming the optimal increment to thedifference. This increment may then be added to the (p+1)th occurrence.Then, the process may be repeated. This may be done until the patternrecognizer predicts logical relationships up to a specified accuracythreshold. Then, the results may be considered optimal.

When a node is at the first level of the hierarchy, its input may comedirectly from the data source, or after some preprocessing. The input toa node at a higher-level may be the concatenation of the outputs of thenodes that are directly connected to it from a lower level. Patterns inhigher-level nodes may represent particular coincidences of their groupsof children. This input may be obtained as a probability distributionfunction (PDF). From this PDF, the probability that a particular groupis active may be calculated as the probability of the pattern that hasthe maximum likelihood among all the patterns belonging to that group.

Various aspects of the systems and methods for practicing features ofthe invention may be implemented on one or more computer systems withprocessors may also execute one or more computer programs to implementvarious functions. These computer programs may be written in any type ofcomputer program language, including a procedural programming language,object-oriented programming language, macro language, or combinationthereof. These computer programs may be stored in storage system.Storage system may hold information on a volatile or non-volatilemedium, and may be fixed or removable and may include a tangiblecomputer-readable and -writable non-volatile recording medium, on whichsignals are stored that define a computer program or information to beused by the program. The recording medium may, for example, be diskmemory, flash memory, and/or any other article(s) of manufacture usableto record and store information. Having thus described several aspectsof at least one embodiment of this invention, it is to be appreciatedthat various alterations, modifications, and improvements will readilyoccur to those skilled in the art. Such alterations, modifications, andimprovements are intended to be part of this disclosure, and areintended to be within the spirit and scope of the invention.Accordingly, the foregoing description and drawings are by way ofexample only.

It should also be appreciated that a computer may be embodied in any ofa number of forms, such as a rack-mounted computer, a desktop computer,a laptop computer, or a tablet computer. Additionally, a computer may beembedded in a device not generally regarded as a computer but withsuitable processing capabilities, including a Personal Digital Assistant(PDA), a smart phone or any other suitable portable or fixed electronicdevice.

Also, a computer may have one or more input and output devices. Thesedevices can be used, among other things, to present a user interface.Examples of output devices that can be used to provide a user interfaceinclude printers or display screens for visual presentation of outputand speakers or other sound-generating devices for audible presentationof output. Examples of input devices that can be used for a userinterface include keyboards, and pointing devices, such as mice, touchpads, and digitizing tablets. As another example, a computer may receiveinput information through speech recognition or in other audible format.

Such computers may be interconnected by one or more networks in anysuitable form, including as a local area network or a wide area network,such as an enterprise network or the Internet. Such networks may bebased on any suitable technology and may operate according to anysuitable protocol and may include wireless networks, wired networks orfiber optic networks.

Also, the various methods or processes outlined herein may be coded assoftware that is executable on one or more processors that employ anyone of a variety of operating systems or platforms. Additionally, suchsoftware may be written using any of a number of suitable programminglanguages and/or programming or scripting tools, and also may becompiled as executable machine language code or intermediate code thatis executed on a framework or virtual machine.

In this respect, the invention may be embodied as a computer-readablemedium (or multiple computer-readable media) (e.g., a computer memory,one or more floppy discs, compact discs (CD), optical discs, digitalvideo disks (DVD), magnetic tapes, flash memories, circuitconfigurations in Field Programmable Gate Arrays or other semiconductordevices, or one or more other non-transitory, tangible computer-readablestorage media) encoded with one or more programs that, when executed onone or more computers or other processors, perform methods thatimplement the various embodiments of the invention discussed above. Thecomputer-readable medium or media may, for example, be transportable,such that the program or programs stored thereon can be loaded onto oneor more different computers or other processors to implement variousaspects of the present invention as discussed above.

The terms “program” or “software” are used herein in a generic sense torefer to any type of computer code or set of computer-executableinstructions that can be employed to program a computer or otherprocessor to implement various aspects of the present invention asdiscussed above. Additionally, it should be appreciated that accordingto one aspect of this embodiment, one or more computer programs thatwhen executed perform methods of the present invention need not resideon a single computer or processor, but may be distributed in a modularfashion amongst a number of different computers or processors toimplement various aspects of the present invention.

Computer-executable instructions may be in many forms, such as programmodules, executed by one or more computers or other devices. Generally,program modules include routines, programs, objects, components, datastructures, etc. that perform particular tasks or implement particularabstract data types. Typically the functionality of the program modulesmay be combined or distributed as desired in various embodiments. Also,data structures may be stored in computer-readable media in any suitableform. For simplicity of illustration, data structures may be shown tohave fields that are related through location in the data structure.Such relationships may likewise be achieved by assigning storage for thefields with locations in a computer-readable medium that conveysrelationship between the fields. However, any suitable mechanism may beused to establish a relationship between information in fields of a datastructure, including through the use of pointers, tags or othermechanisms that establish relationship between data elements.

Various aspects of the present invention may be used alone, incombination, or in a variety of arrangements not specifically discussedin the embodiments described in the foregoing and is therefore notlimited in its application to the details and arrangement of componentsset forth in the foregoing description or illustrated in the drawings.For example, aspects described in one embodiment may be combined in anymanner with aspects described in other embodiments.

Also, the invention may be embodied as a method, of which an example hasbeen provided. The acts performed as part of the method may be orderedin any suitable way. Accordingly, embodiments may be constructed inwhich acts are performed in an order different than that which isillustrated and described, which may include performing some actssimultaneously, even though shown as sequential acts in the illustrativeembodiments described herein.

Use of ordinal terms such as “first,” “second,” “third,” etc., in theclaims to modify a claim element does not by itself connote anypriority, precedence, or order of one claim element over another or thetemporal order in which acts of a method are performed, but are usedmerely as labels to distinguish one claim element having a certain namefrom another element having a same name (but for use of the ordinalterm) to distinguish the claim elements.

Also, the phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having,” “containing,” “involving,” andvariations thereof herein, is meant to encompass the items listedthereafter and equivalents thereof as well as additional items.

It will thus be seen that the objects set forth above, among those madeapparent from the preceding description, are efficiently attained, andsince certain changes may be made in the constructions set forth withoutdeparting from the spirit and scope of the invention, it is intendedthat all matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense. The invention has been described with reference topreferred and alternate embodiments. Modifications and alterations willbecome apparent to those skilled in the art upon reading andunderstanding the detailed discussion of the invention provided herein.This invention is intended to include all such modifications andalterations insofar as they come within the scope of the presentinvention. It is also to be understood that the following claims areintended to cover all of the generic and specific features of theinvention herein described and all statements of the scope of theinvention, which, as a matter of language, might be said to falltherebetween. The invention has been described with reference to thepreferred embodiments. These and other modifications of the preferredembodiments as well as other embodiments of the invention will beobvious from the disclosure herein, whereby the foregoing descriptivematter is to be interpreted merely as illustrative of the invention andnot as a limitation. It is intended to include all such modificationsand alterations insofar as they come within the scope of the appendedclaims.

What is claimed is:
 1. A method for recommending beauty products for asubject, comprising: using a genetic analyzer to generate subjectgenetic information; aggregating genetic information and cosmeticproduct response from the subject; learning with a computer to generateat least one computer implemented classifier including an input layer, apooling layer, and a connected layer that predicts matching beautyproducts based on the genetic information, beauty trend data, andcosmetic product response; and recommending one or more beauty productsfor the subject to apply and treat a cosmetic condition based on agenetic match.
 2. The method of claim 1, wherein the beauty productcomprises skin care product, perfume, hair care product, anti-agingproduct, anti-wrinkle product, makeup product.
 3. The method of claim 1,comprising performing supervised or unsupervised learning selected fromsupport vector machine, random forest, nearest neighbor analysis, linearregression, binary decision tree, discriminant analyses, logisticclassifier and cluster analysis.
 4. The method of claim 1, wherein thegenerated prediction data comprises the development of distantmetastases.
 5. The method of claim 1, comprising processing UICC stage,type of surgical procedure, age, tumor grading, depth of tumorinfiltration, occurrence of post-operative complications, or thepresence of venous mvas10n.
 6. The method of claim 1, wherein theprovided molecular genetic data comprise variables defining the genomicorganization of skin cells and wherein the provided molecular geneticdata comprise variables defining the genomic organization of singledisseminated cells.
 7. The method of claim 1, comprising receiving datafrom sensors that measure lifestyle habits, skin tone, sleepingpatterns, stress, activity, pollution and sun exposure, and receivingdata and analytics to identify beauty trends early using search terms ona search engine; and combining data to offer customers personalizedbeauty advice.
 8. The method of claim 1, wherein pre-processing the datacomprises transformation of the provided data into class-conditionalprobabilities.
 9. The method of claim 1 wherein genetic sequenceinformation comprises sequence and/or abundance data from one or moregenetic loci in cell-free DNA from the individuals.
 10. The method ofclaim 1 wherein beauty product response includes genetic informationfrom the individual generated at a second, later, time point.
 11. Themethod of claim 1, comprising correlating the subject levels ofprofilaggrin alleles present in genome that correspond to differentfilaggrin repeat lengths with predisposition for dry skin as measured byeither their self-perceived frequency of dry skin.
 12. The method ofclaim 11, comprising: i) selecting a group of individuals; ii)identifying in each individual the proportions of profilaggrin allelescorresponding to 10, 11 or 12 filaggrin repeat units encoded by thegenome by analysis of an ex-vivo sample taken from the individual; iii)determining for each individual a measure of predisposition for dry skinby correlating the presence of profilaggrin alleles having either the 11or 12 filaggrin repeat units with susceptibility to dry skin as measuredby one or more of the following methods: a. recording the individual'sself-perceived frequency of dry skin, b. clinically assessing theindividual's leg dryness, or c. determining an individual's rate ofrecovery following a patch test.
 13. The method of claim 11 wherein thecorrelations are determined between the proportion of the individualshaving profilaggrin alleles having no 11 or 12 filaggrin repeat unitsand either the number of individuals having frequent self-perceived dryskin, the number of individuals having leg dryness, or the number ofindividuals exhibiting defined rates of recovery to the SLS patch test.14. The method of claim 1 comprising collection ex-vivo sample from anoral cavity, a nasal cavity, an ear cavity, or behind an ear.
 15. Themethod of claim 1, wherein the genetic analyzer comprises a DNAsequencing machine, a spectrophotometer, a Gas chromatography-massspectrometry (GC-MS) machine, or a gas chromatography-time-of-flightmass spectrometry (GC x GC-TOF MS) machine, comprising generating areport with a description of one or more biological effects and/orvisible signs of the one or more areas of skin health and/or beauty. 16.The method of claim 15, comprising determining a subject's geneticpotential in the one or more areas of skin health and/or beauty byanalyzing one or more skin health-associated genetic markers, such asone or more single nucleotide polymorphisms (SNPs) associated with theone or more areas of skin health and/or beauty being assessed, whereinthe one or more areas of skin health comprise collagen formation, sunprotection, antioxidant protection, glycation protection or inflammationcontrol, collagen formation properties, sun protection properties,antioxidant protection properties, glycation protection properties andinflammation control properties.
 17. The method of claim 1, comprisingreceiving a plurality of genetic information and treatment response overa period of time to see if the treatment improves the subjectcosmetology.
 18. The method of claim 1, comprising recommending beautyor health improvement products for the subject based on geneticinformation and treatment response.
 19. The method of claim 1,comprising identifying skin tumors.
 20. The method of claim 1,comprising receiving genetic information and treatment response over aperiod of time to see if the treatment improves the subject cosmetology.